Bicyclic alkyne derivatives and uses thereof

ABSTRACT

The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazopyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prevention and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, autoimmune diseases, metabolic diseases, and neurodegenerative diseases (e.g. autism, autism spectrum disorders, Alzheimer&#39;s disease)), as well as methods of treating these diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a U.S. National Phase Application under 35U.S.C. § 371 of International Application No. PCT/SG2014/000468, filedOct. 3, 2014, entitled BICYCLIC ALKYNE DERIVATIVES AND USES THEREOF,which claims priority to Great Britain Patent Application No. 1317545.0,filed Oct. 3, 2013.

BACKGROUND OF THE INVENTION

The human MAP Kinase-interacting kinases, also known as MAP Kinasesignal-integrating kinases, (MNKs), are ubiquitously expressedprotein-serine/threonine kinases that are directly activated by ERK orp38 MAP kinases (Buxade, M.; Parra-Palau, J. L.; Proud, C. G. FrontBiosci. 2008, 13, 5359-5373; Fukunaga, R.; Hunter, T. EMBO J. 1997, 16,1921-1933; Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A.EMBO J. 1997, 16, 1909-1920). They comprise a group of four proteinsderived from two genes (gene symbols: MKNK1 and MKNK2) by alternativesplicing. MNK1a/b and MNK2a/b proteins differ at their C-termini, ineach case the a-form has a longer C-terminal region than the b-formwhich lacks the MAP Kinase-binding region. The N-termini of all formscontains a polybasic region which binds importin α and the translationfactor scaffold protein eukaryotic Initiation Factor (eIF4G). Thecatalytic domains of MNK1a/b and MNK2a/b share three unusual features,two short inserts and a DFD motif instead of the most common DFGtripeptide present found on other kinases. MNK isoforms differ markedlyin their activity, regulation and subcellular localization. Thebest-characterized MNK substrate is Eukaryotic Initiation Factor-4 E(eIF4E). Although the cellular role of eIF4E phosphorylation remainsunclear and is thought to promote export of a defined set of mRNAs fromthe nucleus. Other MNK substrates bind to AU-rich elements that modulatethe stability/translation of specific mRNAs. MNK1 is highly expressed inhematological malignancies, and both MNK1 and MNK2 are up-regulated insolid tumors such as gliomas and ovarian cancers (Worch, J.;Tickenbrock, L.; Schwable, J.; Steffen, B.; Cauvet, T.; Mlody, B.;Buerger, H.; Koeffler, H. P.; Berdel, W. E.; Serve, H.; Muller-Tidow, C.Oncogene 2004, 23, 9162-9172; Pellagatti, A.; Esoof, N.; Watkins, F.;Langford, C. F.; Vetrie, D.; Campbell, L. J.; Fidler, C.; Cavenagh, J.D.; Eagleton, H.; Gordon, P.; Woodcock, B.; Pushkaran, B.; Kwan, M.;Wainscoat, J. S.; Boultwood, J. Br. J. Haematol. 2004, 125, 576-583;Bredel, M.; Bredel, C.; Juric, D.; Harsh, G. R.; Vogel, H.; Recht, L.D.; Sikic, B. I. Cancer Res. 2005, 65, 4088-4096; Hendrix, N. D.; Wu,R.; Kuick, R.; Schwartz, D. R.; Fearon, E. R.; Cho, K. R. Cancer Res.2006, 66, 1354-1362).

eIF4E regulates the expression of genes involved in the proliferationand survival as a cap dependent mRNA translation and mRNA export factor.eIF4E is dysregulated in several human cancers, including breast,prostate, and leukemia, and elevated levels of eIF4E are a marker ofpoor prognosis (Nathan, C. O.; Carter, P.; Liu, L.; Li, B. D.; Abreo,F.; Tudor, A.; Zimmer, S. G.; De Benedetti, A. Oncogene 1997, 15,1087-1094; Bianchini, A.; Loiarro, M.; Bielli, P.; Busa, R.; Paronetto,M. P.; Loreni, F.; Geremia, R.; Sette, C. Carcinogenesis 2008, 29,2279-2288; Topisirovic, I.; Guzman, M. L.; McConnell, M. J.; Licht, J.D.; Culjkovic, B.; Neering, S. J.; Jordan, C. T.; Borden, K. L. Mol.Cell Biol. 2003, 23, 8992-9002; Graff, J. R.; Zimmer, S. G. Clin. Exp.Metastasis 2003, 20, 265-273). Moreover, overexpression anddysregulation of eIF4E leads to an increased number of tumors, invasion,and metastases in mouse models¹³ and transgenic expression of eIF4Eleads to a variety of cancers (Graff, J. R.; Zimmer, S. G. Clin. Exp.Metastasis 2003, 20, 265-273; Ruggero, D.; Montanaro, L.; Ma, L.; Xu,W.; Londei, P.; Cordon-Cardo, C.; Pandolfi, P. P. Nat. Med. 2004, 10,484-486). eIF4E overexpression is believed to increase the translationof weakly competitive mRNAs, many of which encode products thatstimulate cell growth and angiogenesis, e.g., fibroblast growth factor 2and vascular endothelial growth factor, cyclin D1, and ribonucleotidereductase (Kevil, C.; Carter, P.; Hu, B.; DeBenedetti, A. Oncogene 1995,11, 2339-2348; Kevil, C. G.; De Benedetti, A.; Payne, D. K.; Coe, L. L.;Laroux, F. S.; Alexander, J. S. Int. J. Cancer 1996, 65, 785-790; Scott,P. A.; Smith, K.; Poulsom, R.; De Benedetti, A.; Bicknell, R.; Harris,A. L. Br. J. Cancer 1998, 77, 2120-2128; Rosenwald, I. B.;Lazaris-Karatzas, A.; Sonenberg, N.; Schmidt, E. V. Mol. Cell Biol.1993, 13, 7358-7363; Abid, M. R.; Li, Y.; Anthony, C.; De Benedetti, A.J. Biol. Chem. 1999, 274, 35991-35998). eIF4E is phosphorylated by theMNK1/2 serine/threonine kinases in response to activation by mitogenicand stress signals downstream of ERK1/2 and p38 MAP kinase respectively(Buxade, M.; Parra-Palau, J. L.; Proud, C. G. Front Biosci. 2008, 13,5359-5373; Fukunaga, R.; Hunter, T. EMBO J. 1997, 16, 1921-1933;Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A. EMBO J. 1997,16, 1909-1920). Thus, inhibitors of MNK1/2 will prevent eIF4Ephosphorylation and therefore could provide a viable therapeuticapproach in high-eIF4E dependent cancers.

Studies have shown that overexpression of eIF4E, as well as eIF4Ephosphorylation, promote cancer cell survival, at least in part byincreasing the level of the anti-apoptotic protein Mcl-1 (Wendel, H. G.;Silva, R. L.; Malina, A.; Mills, J. R.; Zhu, H.; Ueda, T.;Watanabe-Fukunaga, R.; Fukunaga, R.; Teruya-Feldstein, J.; Pelletier,J.; Lowe, S. W. Genes Dev. 2007, 21, 3232-3237; Ueda, T.;Watanabe-Fukunaga, R.; Fukuyama, H.; Nagata, S.; Fukunaga, R. Mol. CellBiol. 2004, 24, 6539-6549). Mcl-1 is a Bcl2 family member with a veryshort half-life, and Mcl-1 mRNA translation highly depends on eIF4E.Thus, it is foreseeable that the inhibition of eIF4E phosphorylation byMNK might induce tumor cells death, as shown for Myc-induced lymphoma.(Wendel, H. G.; Silva, R. L.; Malina, A.; Mills, J. R.; Zhu, H.; Ueda,T.; Watanabe-Fukunaga, R.; Fukunaga, R.; Teruya-Feldstein, J.;Pelletier, J.; Lowe, S. W. Genes Dev. 2007, 21, 3232-3237)

Blast crisis chronic myeloid leukemia (BC-CML) is characterized by anexpansion of a population of granulocyte macrophage progenitor-likecells (GMPs) that have acquired self-renewal capacity, a feature notseen in normal or chronic phase (CP) GMPs and targeting of the MNK-eIF4Eaxis in blast crisis chronic myeloid leukemia inhibits leukemia stemcell function. (Sharon Lim, Tzuen Yih Saw, Min Zhang, Matthew R. Janes,Kassoum Nacro, Jeffrey Hill, An Qi Lim, Chia-Tien Chang, David A.Fruman, David A. Rizzieri, Soo Yong Tan, Hung Fan, c, Charles T. H.Chuah, g, and S. Tiong Ong; N. Proc. Natl. Acad. Sci. U.S.A 2013,110(25), E2298-E2307). The ability to self-renew is thought to bemediated by β-catenin activation, and may contribute to diseasepersistence, as well as initiate drug resistance. It was foundsiRNA-mediated knockdown or inhibition of the MNK1/2 kinases (whichmediate in vivo eIF4E phosphorylation) with small molecules preventedthe increased beta-catenin activity, induced by eIF4E overexpression.These studies suggest that pharmacologic inhibition of the MNK1/2kinases is a plausible therapeutic mean to treat BC CML.

The level of expression of eIF4E and the degree of eIF4E phosphorylationis regulated by pathways that include the P38 kinase, MAPK kinase andAKT/mTOR pathways (Hay, N. Proc. Natl. Acad. Sci. U.S.A 2010, 107,13975-13976). Inhibitors of mTOR such as rapamycin, decrease the levelof phosphorylated eIF4E (Hay, N. Proc. Natl. Acad. Sci. U.S.A 2010, 107,13975-13976). The treatment with rapalogs typically leads to theclinically stable disease or partial remission rather than completetumor regression (Gibbons, J. J.; Abraham, R. T.; Yu, K. Semin. Oncol.2009, 36 Suppl 3, S3-S17). Combination therapy with MNK1/2 and mTORkinases inhibitors could be a viable strategy to treat certain types ofcancer (Wang, X.; Yue, P.; Chan, C. B.; Ye, K.; Ueda, T.;Watanabe-Fukunaga, R.; Fukunaga, R.; Fu, H.; Khuri, F. R.; Sun, S. Y.Mol. Cell Biol. 2007, 27, 7405-7413). WO 2010/055072 discloses MNK andmTOR combination therapy with small molecules, antibodies and siRNA forthe treatment of cancer, and recent findings support that MNK and mTORcombination induces apoptosis in cutaneous T cell lymphoma cells(WO2010055072; Marzec, M.; Liu, X.; Wysocka, M.; Rook, A. H.; Odum, N.;Wasik, M. A. PLoS. One. 2011, 6, e24849).

Macrophages are major effectors of innate immunity, stimulated by abroad variety of bacterial products through specific TLRs on the cellsurface to produce proinflammatory cytokines, such as TNF. E. coli LPSis a potent stimulus to macrophage gene expression, especially TNF, byengaging the TLR4 membrane signaling complex (Hou, L.; Sasaki, H.;Stashenko, P. Infect. Immun. 2000, 68, 4681-4687). It was shown that TLRsignaling pathways require MNK expression through the use of a panel ofcommercial TLR agonist panel on macrophage. TNF production was increasedas a response to Salmonella LPS (TLR4), ODN2006 (TLR9), HKLM (TLR2), FSL(TLR6/2) and imiquimod (TLR7) stimulation. In each case the productionof TNF was inhibited by MNK kinases inhibitor CGP57380 in a dosedependant fashion and the release of multiple innate proinflammatorycytokines were affected, supporting a central role for MNK ininflammation (Rowlett, R. M.; Chrestensen, C. A.; Nyce, M.; Harp, M. G.;Pelo, J. W.; Cominelli, F.; Ernst, P. B.; Pizarro, T. T.; Sturgill, T.W.; Worthington, M. T. Am. J. Physiol Gastrointest. Liver Physiol 2008,294, G452-G459).

MNK inhibitors can regulate the innate immune response in macrophage. Acompound with anti inflammatory properties will inhibit the release ofproinflammatory cytokines. It has been shown that CGP57380, a MNKinhibitor, inhibits the release of TNF alpha by macrophage (and noteIF4E). According to WO2005/003785 MNK kinases are promising targets foranti-inflammatory therapy.

MNK1/2 were also reported to phosphorylate a number of differentproteins in addition to eIF4E. Three of these are hnRNPA1, cPLA2 andSprouty2 (Guil, S.; Long, J. C.; Caceres, J. F. Mol. Cell Biol. 2006,26, 5744-5758; Buxade, M.; Morrice, N.; Krebs, D. L.; Proud, C. G. J.Biol. Chem. 2008, 283, 57-65; Hefner, Y.; Borsch-Haubold, A. G.;Murakami, M.; Wilde, J. I.; Pasquet, S.; Schieltz, D.; Ghomashchi, F.;Yates, J. R., III; Armstrong, C. G.; Paterson, A.; Cohen, P.; Fukunaga,R.; Hunter, T.; Kudo, I.; Watson, S. P.; Gelb, M. H. J. Biol. Chem.2000, 275, 37542-37551; DaSilva, J.; Xu, L.; Kim, H. J.; Miller, W. T.;Bar-Sagi, D. Mol. Cell Biol. 2006, 26, 1898-1907). Their role andfunction is still being investigated. Among these substrates, hnRNPA1 isoverexpressed in colorectal cancer and could contribute to maintenanceof telomere repeats in cancer cells with enhanced cell proliferation(Ushigome, M.; Ubagai, T.; Fukuda, H.; Tsuchiya, N.; Sugimura, T.;Takatsuka, J.; Nakagama, H. Int. J. Oncol. 2005, 26, 635-640). It isalso reported that the expression levels of hnRNPA/B is deregulated innon small cell lung cancer (Boukakis, G.; Patrinou-Georgoula, M.;Lekarakou, M.; Valavanis, C.; Guialis, A. BMC. Cancer 2010, 10, 434).

MNK inhibitors have a substantial potential for the treatment of cancersincluding breast, protate, hematological malignancies (e.g., CML, AML),head and neck, colon, bladder, prostatic adenocarcinoma, lung, cervical,and lymphomas (Soni, A.; Akcakanat, A.; Singh, G.; Luyimbazi, D.; Zheng,Y.; Kim, D.; Gonzalez-Angulo, A.; Meric-Bernstam, F. Mol. Cancer Ther.2008, 7, 1782-1788; Berkel, H. J.; Turbat-Herrera, E. A.; Shi, R.; DeBenedetti, A. Cancer Epidemiol. Biomarkers Prev. 2001, 10, 663-666;Wendel, H. G.; De Stanchina, E.; Fridman, J. S.; Malina, A.; Ray, S.;Kogan, S.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S. W. Nature 2004,428, 332-337; De Benedetti, A.; Graff, J. R. Oncogene 2004, 23,3189-3199).

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds that act askinase inhibitors, in particular as inhibitors of the MAP kinaseinteracting kinases 1 and 2 (MNK1 and MNK2). These compounds may beuseful in the treatment of various disease associated with kinaseactivity such as proliferative disorders (e.g., cancer), autoimmunedisorders, inflammatory-disorders, metabolic disorders, and neurologicaldisorders.

In certain embodiments, a compound of the present invention is ofFormula (I):

or a pharmaceutically acceptable form (such as pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, and prodrugs thereof,wherein R¹, Ring A, X₁, X₂, X₃, and X₄ are as described herein. Incertain embodiments, the pharmaceutical acceptable form ispharmaceutically acceptable salt. These compound are useful in treatingproliferative diseases (e.g. cancer including hematological cancers andsolid tumors), inflammatory diseases, neurodegenerative diseases (e.g.Alzheimer's disease, autism, or autism spectrum disorders (e.g. Aspergersyndrome or Mendelsohnn's Syndrome), and metabolic disorders (e.g.obesity, diabetes).

In certain embodiments, the provided compound is of formula

wherein R^(pa), R^(pb), R^(pc), R^(pd), R^(pe), Ring A, X₁, X₂, X₃, andX₄ are as described herein.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising an inventive compound, and optionally apharmaceutically acceptable excipient, and to their use for treatingdiseases associated with aberrant MNK1 or MNK2 activity or dysregulationof the MNK1 or MNK2 pathway, where MNK1 and MNK2 play a role (MNKoverexpression, eIF4E overexpression, P38 MAPK kinase pathway).Exemplary MNK-related disorders include, but are not limited to,metabolic diseases such as obesity, as well as related disorders such aseating disorder, cachexia, diabetes mellitus, hypertension, coronaryheart disease, hypercholesterolemia, dyslipidemia, osteoarthritis,gallstones, and sleep apnea, neurodegenerative disorders such asAlzheimer's disease, autism, or autism spectrum disorders (e.g. Aspergersyndrome or Mendelsohnn's Syndrome), and cancer such as breast,prostate, hematological malignancies (e.g., CML, AML, lymphomas), headand neck, colon, bladder, prostatic adenocarcinoma, lung, cervical, andlymphomas.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising an inventive compound, and optionally apharmaceutically acceptable excipient, and to their use for theprevention and treatment of a PI3-kinase (PI3K)-related disorder. Incertain embodiments, the PI3K-related disorder is PI3K α-relateddisorder. In certain embodiments, the PI3K-related disorder is PI3Kβ-related disorder. In certain embodiments, the PI3K-related disorder isPI3K γ-related disorder. In certain embodiments, the PI3K-relateddisorder is PI3K δ-related disorder. Exemplary PI3K-related disordersinclude, but are not limited to, cancers such as ovarian cancer,cervical cancer, breast cancer, colon cancer, rectal cancer, endometrialcancer, stomach cancer, liver cancer, lung cancer, thyroid cancer, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), andglioblastomas.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for theprevention and treatment of a Janus kinase (JAK)-related disorder. Incertain embodiments, the JAK-related disorder is JAK1-related disorder.In certain embodiments, the JAK-related disorder is JAK2-relateddisorder. In certain embodiments, the JAK-related disorder isJAK3-related disorder. Exemplary JAK-related disorders include, but arenot limited to, psoriasis, rheumatoid arthritis, and cancers such asprostate, colon, ovarian and breast cancers, melanoma, leukemia andother hematological malignancies.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for theprevention and treatment of a Human Epidermal Growth FactorReceptor-related (HER-) disorder. In certain embodiments, theHER-related disorder is HER2-related disorder. In certain embodiments,the HER-related disorder is HER3-related disorder. Exemplary HER-relateddisorders include, but are not limited to, cancers such as breast, lung,kidney, brain, ovarian, colon, cervical, endometrial, prostate, liver,thyroid, GI tract, blood and lymphoma and other diseases such asmultiple sclerosis.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for theprevention and treatment of an mTOR-related disorder. ExemplarymTOR-related disorders include, but are not limited to, cancers, such asbreast, lung, kidney, brain, ovarian, colon, cervical, endometrial,prostate, liver, thyroid, GI tract, hematological cancers, and lymphoma,and other diseases such as hamartoma syndromes, rheumatoid arthritis,and multiple sclerosis.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for theprevention and treatment of diseases such as, but not limited to,proliferative diseases, cancer (e.g., hematological cancers, non-solidcancers, and solid tumors), inflammatory diseases, neurodegenerativediseases (e.g., Alzheimer's disease, autism, or autism spectrumdisorders (e.g. Asperger syndrome or Mendelsohnn's Syndrome), metabolicdisorders (obesity, diabetes) as well as methods of treating thesedisorders using compounds described herein as single agents or incombination with one or more additional agents. In some embodiments, theadditional agent is a kinase inhibitor. In some embodiments, theadditional agent is an mTOR inhibitor (e.g., Sirolimus (rapamycin),Temsirolimus (CC1779), Everolimus (RAD001), AP23573 or other compoundsdisclosed in U.S. Pat. No. 7,091,213). In some embodiments, theadditional agent is a PI3K inhibitor. Exemplary PI3-kinase inhibitorsinclude wortmannin, demethoxyviridin, LY294002, perifosine, CAL101,PX-886, BEZ235, SF1126, INK1117, INK1197, IPI-145, GDC-0941, BKM120,XL147, XL765, palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114,TG100-115, CAL263, PI-103, GNE-477, CUDC-907, GSK 2126458, GDC-0980,PF-46915032, CAL263, SF1126 and PX-886. In some embodiments, thePI3-kinase inhibitor inhibits PI3K-α, PI3K-β, PI3K-γ, and/or PI3K-δ.

In yet another aspect, the present invention describes methods for thesynthesis of compounds of Formula (I), such as, for example,(4-methylpiperazin-1-yl)(4-(3-(phenylethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)methanoneand4-methyl-2-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)ethynyl)benzonitrile.

In another aspect, the present invention provides kits comprising acompound as described herein, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition thereof. The provided kits maybe useful for the treatment of proliferative diseases, cancer (e.g.,hematological cancers, non-solid cancers, and solid tumors),inflammatory diseases, neurodegenerative diseases (e.g., Alzheimer'sdisease, autism, or autism spectrum disorders (e.g. Asperger syndrome orMendelsohnn's Syndrome)), and metabolic disorders (e.g., obesity,diabetes). In certain embodiments, the kits described herein furtherinclude instructions for administering the compound as described herein,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof. The kits may also include packaging informationdescribing the use or prescribing information for the subject or ahealth care professional. Such information may be required by aregulatory agency such as the U.S. Food and Drug Administration (FDA).The kit may also optionally include a device for administration of thecompound or composition, for example, a syringe for parenteraladministration.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the cellular pathways that lead to eIF4E activationand phosphorylation by MNK1/2 (PNAS, 2010, 107(32): 13975-6).

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents. In certain embodiments, the alkyl group isunsubstituted C₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₁₀ alkyl.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₅), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or a fused, bridged or spiro ring system such as a bicyclic system(“bicyclic heterocyclyl”), and can be saturated or can be partiallyunsaturated. Heterocyclyl bicyclic ring systems can include one or moreheteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocyclyl ring, as defined above, is fused withone or more carbocyclyl groups wherein the point of attachment is eitheron the carbocyclyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system. Unless otherwise specified, each instance of heterocyclylis independently optionally substituted, i.e., unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. Incertain embodiments, the heterocyclyl group is substituted 3-10 memberedheterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 nelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted(“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; each instance of R^(ff) is, independently, selected fromhydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, or two R^(ff) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; andeach instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆alkyl, —SC(═S)SC₁₋₆alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc), and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Amide nitrogen protecting groups (e.g., —C(═O)R^(aa)) include, but arenot limited to, formamide, acetamide, chloroacetamide,trichloroacetamide, trifluoroacetamide, phenylacetamide,3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide,N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide,o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide,(N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide,3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine,o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Carbamate nitrogen protecting groups (e.g., —C(═O)OR^(aa)) include, butare not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate. (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl, thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Sulfonamide nitrogen protecting groups (e.g., —S(═O)₂R^(aa)) include,but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The present invention isnot intended to be limited in any manner by the above exemplary listingof substituents.

Other Definitions

The term “pharmaceutically acceptable form thereof” as used hereinrefers to pharmaceutically acceptable salts, solvates, hydrates,prodrugs, tautomers, isomers, enantiomers, diastereomers, and/orpolymorphs of a compound of the present invention.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. The term “pharmaceutically acceptablesalt” as used herein refers to those salts which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof humans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al., describe pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,incorporated herein by reference. Pharmaceutically acceptable salts ofthe compounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

In certain embodiments, the pharmaceutically acceptable form is ahydrate or solvate. The term “hydrate” as used herein refers to acompound non-covalently associated with one or more molecules of water.Likewise, the term “solvate” refers to a compound non-covalentlyassociated with one or more molecules of an organic solvent.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. The term “prodrug” as used herein refers to a derivative of aparent compound that requires transformation within the body in order torelease the parent compound. In certain cases, a prodrug has improvedphysical and/or delivery properties over the parent compound. Prodrugsare typically designed to enhance pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it may enhance drug stabilityfor long-term storage. In recent years several types of bioreversiblederivatives have been exploited for utilization in designing prodrugs.Using esters as a prodrug type for compounds containing a carboxyl orhydroxyl functionality is known in the art as described, for example, inThe Organic Chemistry of Drug Design and Drug Interaction by RichardSilverman, published by Academic Press (1992).

In certain embodiments, the pharmaceutically acceptable form is atautomer. The term “tautomer” as used herein includes two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim;enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.

In certain embodiments, the pharmaceutically acceptable form is anisomer. The term “isomer” as used herein includes any and all geometricisomers and stereoisomers (e.g., enantiomers, diasteromers, etc.). Forexample, “isomer” include cis- and trans-isomers, E- and Z-isomers, R-and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. For instance, an isomer/enantiomer may, in someembodiments, be provided substantially free of the correspondingenantiomer, and may also be referred to as “optically enriched.”“Optically-enriched,” as used herein, means that the compound is made upof a significantly greater proportion of one enantiomer. In certainembodiments the compound of the present invention is made up of at leastabout 90% by weight of a preferred enantiomer. In other embodiments thecompound is made up of at least about 95%, 98%, or 99% by weight of apreferred enantiomer. Preferred enantiomers may be isolated from racemicmixtures by any method known to those skilled in the art, includingchiral high pressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts or prepared by asymmetric syntheses.See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972).

In certain embodiments, the pharmaceutically acceptable form is apolymorph. The term “polymorph” as used herein refers to a crystallinecompound existing in more than one crystalline form/structure. Whenpolymorphism exists as a result of difference in crystal packing it iscalled packing polymorphism. Polymorphism can also result from theexistence of different conformers of the same molecule in conformationalpolymorphism. In pseudopolymorphism the different crystal types are theresult of hydration or solvation.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, and/or turkeys. In certainembodiments, the subject is an animal. The animal may be of either sexand may be of any stage of development. In certain embodiments, theanimal is a mammal. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a domesticated animal, such as adog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, thesubject is a companion animal such as a dog or cat. In certainembodiments, the subject is a livestock animal such as a cow, pig,horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal such asa rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certainembodiments, the animal is a genetically engineered animal. In certainembodiments, the animal is a transgenic animal.

“Treat,” “treating” and “treatment” encompasses an action that occurswhile a subject is suffering from a condition (e.g., a “MNK1- orMNK2-related” disease, disorder, or condition, e.g., a disease,disorder, or condition in which MNK1 and/or MNK2 is known to play role)which reduces the severity of the condition or retards or slows theprogression of the condition (“therapeutic treatment”).

As used herein “inhibition,” “inhibiting,” and “inhibit”, refer to theability of a compound to reduce, slow, halt, or prevent the activity ofa particular biological process relative to a control. In certainembodiments, the biological process is in vitro (e.g., a biochemical orcellular assay). In certain embodiments, the biological process is invivo.

An “effective amount” of a compound refers to an amount sufficient toelicit the desired biological response, e.g., treat the condition. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound described herein may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the condition being treated, the mode of administration,and the age and health of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

A “therapeutically effective amount” of a compound is an amountsufficient to provide a therapeutic benefit in the treatment of acondition or to delay or minimize one or more symptoms associated withthe condition. A therapeutically effective amount of a compound means anamount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of the condition, or enhances the therapeutic efficacy of anothertherapeutic agent. In some embodiments, a therapeutically effectiveamount is an amount effective to inhibit cell growth or induce celldeath.

A “prophylactically effective amount” of a compound is an amountsufficient to prevent a condition, or one or more symptoms associatedwith the condition or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of a therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the condition. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, the term “kinase” represent a class of enzymes that areable to transfer a phosphate group from a donor molecule to an acceptormolecule, e.g., an amino acid residue of a protein or a lipid molecule.Representative, non-limiting examples of kinases include Abl, ACK,Akt1/PKBα, Akt2/PKBβ, Akt3/PKBγ, ALK1, ALK2, Alk4, AMPKα1/β1/γ1,AMPKα1/β1/γ2, AMPKα1/β1/γ3, AMPKα1/β2/γ1, AMPKα2/β1/γ1, AMPKα2/β2/γ2,Abl2, ARKS, Ask1, Aurora A, Aurora B, Aurora C, Axl, BARK1, Blk, Bmx,B-Raf, Brk, BrSK1, BrSK2, Btk, CaMK1α, CaMK1β, CaMK1γ, CaMK1δ, CAMK2α,CaMK2β, CAMK2δ, CAMK2γ, CAMK4, CAMKK1, CAMKK2, CDK1, CDK2, CDK3, CDK4,CDK5, CDK6, CDK7, CDK9, CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E,CDK3/cyclin E, CDK5/p25, CDK5/p35, CDK6/cyclinD3, CDK7/cyclin H/MAT1,CDK9/cyclin T1, CHK1, CHK2, CK1(γ), CK1δ, CK2α1, CK2α2, cKit, c-RAF,CLK1, CLK2, CLK3, COT, Csk, DAPK1, DAPK2, DAPK3, DCAMLK2, DDR2, DMPK,DRAK1, DYRK1A, DYRK2, DYRK3, eEF2K, EGFR, EPHA1, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EphB1, EphB2, EphB3, EphB4, ErbB4, Erk1,Erk2, FAK, Fer, Fes, FGFR1, Flt2, Flt4, FLT3 D835Y, FGFR2, FGFR3, FGFR4,Fgr, Flt1, Flt3, Fms, FRK, FynA, GCK, GPRK5, GRK2, GRK4, GRK6, GRK7,GSK3α, GSK3β, Hck, HER2, HER4, HIPK1, HIPK2, HIPK3, HIPK4, IGF1R, IKKβ,IKKα, IKKε, IR, InsR, IRR, IRAK1, IRAK2, IRAK4, Itk, JAK2, JAK3, JNK1,JNK2, JNK3, KDR, KHS1, Kit, Lck, LIMK1, LKB1, LOK, LRRK2, Lyn A, Lyn B,MAPK1, MAPK2, MAPK12, MAPKAP-K2, MAPKAP-K3, MAPKAPK2, MAPKAPK3,MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MELK, MEK1, MEK2, MEKK2, MEKK3,Mer, Met, MET M1250T, MINK, MKK4, MKK6, MKK7β, MLCK, MLK1, MLK3, MNK1,MNK2, MRCKα, MRCKβ, MSK1, MSK2, MSSK1, STK23, STK4, STK3, STK24, MST1,MST2, MST3, MST4, MUSK, mTOR, MYO3β, MYT1, NDR1, NEK11, NEK2, NEK3,NEK6, NEK7, NEK9, NLK, NUAK2, p38α, p38β, p38δ, p38γ, p70S6K, S6K, SRK,PAK1/CDC42, PAK2, PAK3, PAK4, PAK5, PAK6, PAR-1Bα, PASK, PBK, PDGFRα,PDGFRPβ, PDK1, PEK, PHKG2, PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ, Pim1, Pim2,PKAcα, PKAcβ, PKAcγ, PKA(b), PKA, PKBα, PKBβ, PKBγ, PKCα, PKCPβ1,PKCPβ2, PKCPβ11, PKCδ, PKCε, PKCγ, PKCμ, PKCΘ, PKCι, PKCθ, PKCζ, PKD1,PKD2, PKD3, PKG1α, PKG1B, PKN1, PKN2, PKR, PLK1, PLK2, PLK3, PLK4, Polo,PRAK, PRK2, PrKX, PTK5, PYK2, QIK, Raf1, Ret, RIPK2, RIPK5, ROCK1,ROCK2, RON, ROS, Rse, RSK1, RSK2, RSK3, RSK4, SAPK2a, SAPK2b, SAPK3,SAPK4, SGK1, SGK2, SGK3, SIK, MLCK, SLK, Snk, Src, SRPK1, SRPK2, STK33,SYK, TAK1-TAB1, TAK1, TBK1, TAO1, TAO2, TAO3, TBK1, TEC, TESK1, TGFβR1,TGFβR2, Tie2, TLK2, TrkA, TrkB, TrkC, TSSK1, TSSK2, TTK, TXK, TYK2,TYRO3, ULK1, ULK2, WEE1, WNK2, WNK3, Yes1, YSK1, ZAK, ZAP70, ZC3, andZIPK.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis or diseases associated withangiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An example of a pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites.

The term “metastasis,” “metastatic,” or “metastasize” refers to thespread or migration of cancerous cells from a primary or original tumorto another organ or tissue and is typically identifiable by the presenceof a “secondary tumor” or “secondary cell mass” of the tissue type ofthe primary or original tumor and not of that of the organ or tissue inwhich the secondary (metastatic) tumor is located. For example, aprostate cancer that has migrated to bone is said to be metastasizedprostate cancer and includes cancerous prostate cancer cells growing inbone tissue.

As used herein, the term “cancer” refers to a malignant neoplasm(Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990). Exemplary cancers include, but are not limited to,acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer;angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliarycancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,adenocarcinoma of the breast, papillary carcinoma of the breast, mammarycancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma,oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma); connective tissue cancer;epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi'ssarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer(e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarinoma); Ewing'ssarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g.,prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary glandcancer; skin cancer (e.g., squamous cell carcinoma (SCC),keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowelcancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignantfibrous histiocytoma (MFH), liposarcoma, malignant peripheral nervesheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma);sebaceous gland carcinoma; small intestine cancer; sweat glandcarcinoma; synovioma; testicular cancer (e.g., seminoma, testicularembryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of thethyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer);urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget'sdisease of the vulva).

The term “angiogenesis” refers to the formation and growth of new bloodvessels. Normal angiogenesis occurs in the body of a healthy subjectduring wound healing and for restoring blood flow to tissues afterinjury. The body controls angiogenesis through a number of means, e.g.,angiogenesis-stimulating growth factors and angiogenesis inhibitors.Many disease states, such as cancer, diabetic blindness, age-relatedmacular degeneration, rheumatoid arthritis, and psoriasis, arecharacterized by abnormal (i.e., increased or excessive) angiogenesis.Abnormal angiogenesis refers to angiogenesis greater than that in anormal body, especially angiogenesis in an adult not related to normalangiogenesis (e.g., menstruation or wound healing). Abnormalangiogenesis can result in new blood vessels that feed diseased tissuesand/or destroy normal tissues, and in the case of cancer, the newvessels can allow tumor cells to escape into the circulation and lodgein other organs (tumor metastases).

As used herein, an “inflammatory disease” refers to a disease caused by,resulting from, or resulting in inflammation. The term “inflammatorydisease” may also refer to a dysregulated inflammatory reaction thatcauses an exaggerated response by macrophages, granulocytes, and/orT-lymphocytes leading to abnormal tissue damage and/or cell death. Aninflammatory disease can be either an acute or chronic inflammatorycondition and can result from infections or non-infectious causes.Inflammatory diseases include, without limitation, atherosclerosis,arteriosclerosis, autoimmune disorders, multiple sclerosis, systemiclupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,degenerative arthritis, tendonitis, bursitis, psoriasis, cysticfibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis,Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis(scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis,pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis,Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixedconnective tissue disease, sclerosing cholangitis, inflammatory boweldisease, Crohn's disease, ulcerative colitis, pernicious anemia,inflammatory dermatoses, usual interstitial pneumonitis (UIP),asbestosis, silicosis, bronchiectasis, berylliosis, talcosis,pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia,lymphoid interstitial pneumonia, giant cell interstitial pneumonia,cellular interstitial pneumonia, extrinsic allergic alveolitis,Wegener's granulomatosis and related forms of angiitis (temporalarteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis,delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis),pneumonia, respiratory tract inflammation, Adult Respiratory DistressSyndrome (ARDS), encephalitis, immediate hypersensitivity reactions,asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever,glomerulonephritis, pyelonephritis, cellulitis, cystitis, chroniccholecystitis, ischemia (ischemic injury), reperfusion injury, allograftrejection, host-versus-graft rejection, appendicitis, arteritis,blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis,sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis,urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis,angitis, chronic bronchitis, osteomylitis, optic neuritis, temporalarteritis, transverse myelitis, necrotizing fascilitis, and necrotizingenterocolitis.

As used herein, an “autoimmune disease” refers to a disease arising froman inappropriate immune response in the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppressants, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis, psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, perphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), urveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “autoinflammatory disease” refers to a category of diseasesthat are similar but different from autoimmune diseases.Autoinflammatory and autoimmune diseases share common characteristics inthat both groups of disorders result from the immune system attacking asubject's own tissues and result in increased inflammation. Inautoinflammatory diseases, a subject's innate immune system causesinflammation for unknown reasons. The innate immune system reacts eventhough it has never encountered autoantibodies or antigens in thesubject. Autoinflammatory disorders are characterized by intenseepisodes of inflammation that result in such symptoms as fever, rash, orjoint swelling. These diseases also carry the risk of amyloidosis, apotentially fatal buildup of a blood protein in vital organs.Autoinflammatory diseases include, but are not limited to, familialMediterranean fever (FMF), neonatal onset multisystem inflammatorydisease (NOMID), tumor necrosis factor (TNF) receptor-associatedperiodic syndrome (TRAPS), deficiency of the interleukin-1 receptorantagonist (DIRA), and Behçet's disease.

The term “neurodegenerative disease” as used herein refers to motorneuron diseases represented by amyotrophic lateral sclerosis,Parkinson's syndrome including Parkinson's disease, dementia representedby Alzheimer's disease, progressive supranuclear palsy, Huntington'sdisease, multiple system atrophy including striatonigral degeneration,Shy-Drager syndrome and olivopontocerebellar atrophy, any type ofspinocerebellar ataxia including spinocerebellar ataxia type 1,spinocerebellar ataxia type 2, spinocerebellar ataxia type 3(Machado-Joseph disease, MJD), spinocerebellar ataxia type 6,spinocerebellar ataxia type 7, spinocerebellar ataxia type 12 anddentatorubral-pallidoluysian atrophy, or multiple sclerosis, as well asautism and autism spectrum disorders (e.g. Asperger syndrome orMendelsohnn's Syndrome)

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The invention provides bicyclic alkyne derivatives as kinase inhibitors.In particular, the provided compounds act as inhibitors of the MAPkinase interacting kinases 1 and 2 (MNK1 and/or MNK2). The providedcompounds and pharmaceutical compositions thereof are useful in treatingdiseases associated with aberrant MNK1 or MNK2 activity or dysregulationof the MNK1 or MNK2 pathway, where MNK1 and MNK2 play a role (e.g. MNKoverexpression, eIF4E overexpression, P38 MAPK kinase pathway). Forexample, the provided compounds and pharmaceutical compositions can beused to prevent and/or treat cancer (such as solid tumor, non-solidcancers, and hematological cancers), an inflammatory disease, aneurodegenerative disease (such as Alzheimer's. autism, or autismspectrum disorders (e.g. Asperger syndrome or Mendelsohnn's Syndrome),or a metabolic disorder (such as diabetes, hyperlipidemia and obesity).

Compounds

In one aspect, the present invention provides a compound of Formula (I):

or a pharmaceutically acceptable form thereof (such as pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, and prodrugs thereof),wherein

X₁ and X₂ are independently N or C;

X₃ and X₄ are independently N or CR²;

provided that at least two of X₁, X₂, X₃, and X₄ are N;

is a single or double bond, as valency allows;

R¹ is independently hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ carbocyclyl, optionally substituted phenyl,optionally substituted six-membered heteroaryl, optionally substitutedsix-membered heterocyclyl, optionally substituted C₃₋₆ carbocyclylalkyl,optionally substituted arylalkyl, optionally substituted five- orsix-membered heteroarylalkyl, optionally substituted five- orsix-membered heterocyclylalkyl, —CN, —OR^(A), or —N(R^(B))₂;

each instance of R² is independently hydrogen, halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl,—OR^(A), or —N(R^(B))₂,

Ring A is optionally substituted phenyl, optionally substitutedfive-membered heteroaryl, optionally substituted six-memberedheteroaryl, or optionally substituted 5,6-bicyclic heteroaryl;

each instance of R^(A) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or an oxygen protecting group; and

each instance of R^(B) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteraryl, optionally substituted acyl, or a nitrogenprotecting group.

In certain embodiments, the pharmaceutical acceptable form ispharmaceutically acceptable salt.

As generally defined herein, R¹ is independently hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl,optionally substituted phenyl, optionally substituted six-memberedheteroaryl, optionally substituted six-membered heterocyclyl, optionallysubstituted C₃₋₆ carbocyclylalkyl, optionally substituted arylalkyl,optionally substituted five- or six-membered heteroarylalkyl, optionallysubstituted five- or six-membered heterocyclylalkyl, —CN, —OR^(A), or—N(R^(B))₂. In some embodiments, R¹ is hydrogen. In some embodiments, R¹is optionally substituted C₁₋₆alkyl. In some embodiments, R¹ issubstituted C₁₋₆ alkyl. In some embodiments, R¹ is unsubstituted C₁₋₆alkyl. In some embodiments, R¹ is methy, ethyl, n-propyl, or iso-propyl.In some embodiments, R¹ is optionally substituted C₃₋₆ carbocyclyl. Insome embodiments, R¹ is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, R¹ is independently optionallysubstituted phenyl, optionally substituted six-membered heteroaryl, oroptionally substituted six-membered heterocyclyl.

In some embodiments, R¹ is optionally substituted phenyl of the formula:

wherein

each instance of R^(1a) is independently hydrogen, halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl,optionally substituted phenyl, optionally substituted five- orsix-membered heteroaryl, optionally substituted five- or six-memberedheterocyclyl, optionally substituted acyl, —CN, —OR^(A), or —N(R^(B))₂;and

m1 is an integer of 1 to 5, inclusive.

In some embodiments, R^(1a) is of the formula

wherein R^(1d) is optionally substituted six-membered heterocyclyl,—OR^(A), or —N(R^(B))₂, wherein R^(A) and R^(B) are defined herein.

In certain embodiments, R¹ is of the formula:

wherein

R^(pa) is hydrogen, halogen, CN, optionally substituted C₁₋₆ alkyl,—OR^(A), —N(R^(B))₂, —NH—CO—R^(C);

R^(C) is optionally substituted C₁₋₆ alkyl;

R^(pb) is independently hydrogen, halogen, CN, —OR^(A), —N(R^(B))₂,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆carbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl;

each of R^(pc) and R^(pd) is independently hydrogen, halogen, CN,—OR^(A), or optionally substituted C₁₋₆ alkyl;

or R^(pc) and R^(pd) are joined to form ═O; and

R^(pe) is optionally substituted six-membered heterocyclyl, —OR^(A), or—N(R^(B))₂; and

each instance of R^(A) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or an oxygen protecting group; and each instanceof R^(B) is independently hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted heteraryl,optionally substituted acyl, or a nitrogen protecting group.

In certain embodiments, R^(pc) and R^(pd) are joined to form ═O and R¹is of the formula:

each instance of R^(1d) is optionally substituted six-memberedheterocyclyl, —OR^(A), or —N(R^(B))₂.

In certain embodiments, R^(pa) is hydrogen and R^(pb) is halogen. Incertain embodiments, R^(pa) is hydrogen and R^(pb) is F. In certainembodiments, R^(pa) is hydrogen and R^(pb) is Cl. In certainembodiments, R^(pa) is hydrogen and R^(pb) is Br. In certainembodiments, R^(pa) is hydrogen and R^(pb) is I. In certain embodiments,R^(pb) is hydrogen and R^(pa) is halogen. In certain embodiments, R^(pb)is hydrogen and R^(pa) is F. In certain embodiments, R^(pb) is hydrogenand R^(pa) is Cl. In certain embodiments, R^(pb) is hydrogen and R^(pa)is Br. In certain embodiments, R^(pb) is hydrogen and R^(pa) is I.

In certain embodiments, R^(pa) and R^(pb) are both hydrogen. In certainembodiments, R¹ is of the formula:

wherein each instance of R^(1d) is optionally substituted six-memberedheterocyclyl, —OR^(A), or —N(R^(B))₂.

In certain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted six-membered heterocyclyl,—OR^(A), or —N(R^(B))₂. In certain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted six-membered heterocyclyl. Incertain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted morpholine or optionallysubstituted piperazine. In certain embodiments, In certain embodiments,R¹ is of the formula:

wherein R^(1d) is —N(R^(B))₂, and each instance of R^(B) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted acyl, or a nitrogen protecting group. In certainembodiments, R¹ is of the formula:

and R^(1d) is hydrogen. In certain embodiments, R¹ is one of thefollowing formulae:

In certain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted six-membered heterocyclyl,—OR^(A), or —N(R^(B))₂. In certain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted six-membered heterocyclyl. Incertain embodiments, R¹ is of the formula:

wherein R^(1d) is optionally substituted morpholine or optionallysubstituted piperazine. In certain embodiments, R¹ is of the formula:

wherein R^(1d) is —N(R^(B))₂, and each instance of R^(B) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted acyl, or a nitrogen protecting group. In certainembodiments, R¹ is of the formula

In some embodiments, R¹ is optionally substituted six-memberedheteroaryl. In certain embodiments, R¹ is one of the following formulae:

wherein R^(1a) is as defined herein; and each instance of m2 isindependently an integer of 1 to 4, inclusive.

As generally defined herein, m2 is an integer of 1 to 4, inclusive. Incertain embodiments, m2 is 1. In certain embodiments, m2 is 2. Incertain embodiments, m2 is 3. In certain embodiments, m2 is 4.

In some embodiments, R¹ is optionally substituted six-memberedheterocyclyl. In some embodiments, R¹ is one of the following formulae:

wherein each instance of R^(1a) is as defined herein; each instance ofm3 is independently an integer of 1 to 8, inclusive; and R^(N) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted acyl, or a nitrogen protecting group.

In certain embodiments, the provided compound of Formula (I) is ofFormula (I-i):

R^(pa) is hydrogen, halogen, CN, optionally substituted C₁₋₆ alkyl,—OR^(A), —N(R^(B))₂, —NH—CO—R^(C);

R^(C) is optionally substituted C₁₋₆ alkyl;

R^(pb) is independently hydrogen, halogen, CN, —OR^(A), —N(R^(B))₂,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆carbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl;

each of R^(pc) and R^(pd) is independently hydrogen, halogen, CN,—OR^(A), or optionally substituted C₁₋₆ alkyl;

or R^(pc) and R^(pd) are joined to form ═O; and

R^(pe) is optionally substituted six-membered heterocyclyl, —OR^(A), or—N(R^(B))₂; and

each instance of R^(A) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or an oxygen protecting group; and

each instance of R^(B) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteraryl, optionally substituted acyl, or a nitrogenprotecting group.

As generally defined herein, m3 is an integer of 1 to 8, inclusive. Incertain embodiments, m3 is 1. In certain embodiments, m3 is 2. Incertain embodiments, m3 is 3. In certain embodiments, m3 is 4. Incertain embodiments, m3 is 5. In certain embodiments, m3 is 6. Incertain embodiments, m3 is 7. In certain embodiments, m3 is 8.

As generally used herein, R^(N) is independently hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl,optionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted acyl, or anitrogen protecting group. In certain embodiments, R^(N) is hydrogen,optionally substituted C₁₋₆ alkyl, or an oxygen protecting group. Incertain embodiments, R^(N) is hydrogen. In certain embodiments, R^(N) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R^(N) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(N) is methyl orethyl. In certain embodiments, R^(N) is a nitrogen protecting group. Incertain embodiments, R^(N) is Bn, BOC, Cbz, or Fmoc.

In certain embodiments, R¹ is of the formula;

In certain embodiments, R¹ is optionally substituted six-memberedheterocyclylalkyl. In certain embodiments, R¹ is one of the followingformulae:

wherein R^(1a) is as define herein; each instanced of R^(1b) and R^(1c)is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —CN,—OR^(A), or —N(R^(B))₂; each instance of m4 is independently an integerof 1 to 8, inclusive, as valency permits; and R^(N) is as definedherein.

As generally defined herein, m4 is an integer of 1 to 8, inclusive. Incertain embodiments, m4 is 1. In certain embodiments, m4 is 2. Incertain embodiments, m4 is 3. In certain embodiments, m4 is 4. Incertain embodiments, m4 is 5. In certain embodiments, m4 is 6. Incertain embodiments, m4 is 7. In certain embodiments, m4 is 8.

As generally defined herein, each of R^(1b) and R^(1c) is independentlyhydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —CN, —O^(RA), or—N(^(RB))₂, wherein R^(A) and R^(B) are as defined herein. In certainembodiments, R^(1b) and R^(1c) are both hydrogen.

In certain embodiments, R¹ is one of the following formulae:

In certain embodiments, R¹ is —N(R^(B))₂, wherein each instance of R^(B)is independently hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteraryl, optionallysubstituted acyl, or a nitrogen protecting group. In certainembodiments, R¹ is —N(R^(B))₂, wherein each instance of R^(B) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, or optionallysubstituted acyl. In certain embodiments, R¹ is —NHR^(B), wherein R^(B)is hydrogen, optionally substituted C₁₋₆ alkyl, or optionallysubstituted acyl. In certain embodiments, R¹ is NH₂. In certainembodiments, R¹ is —NHR^(B), wherein R^(B) is optionally substitutedC₁₋₆ alkyl. In certain embodiments, R¹ is —N(CH₃)₂. In certainembodiments, R¹ is —NHR^(B), wherein R^(B) is optionally substitutedacyl. In certain embodiments, R¹ is —NHAc.

As generally defined herein, Ring A is optionally substituted phenyl,optionally substituted five-membered heteroaryl, optionally substitutedsix-membered heteroaryl, or optionally substituted 5,6-bicyclicheteroaryl.

In certain embodiments, Ring A is of the formula:

wherein

a indicates the point of attachment to the alkyne;

each instance of R^(RA) is independently hydrogen, halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted acyl, —CN, —OR^(AO), or—N(R^(AN))₂;

each instance of R^(AO) is independently hydrogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or an oxygen protecting group;

each instance of R^(AN) is independently hydrogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteraryl, optionally substituted acyl, or a nitrogenprotecting group; and

n1 is an integer of 1 to 5, inclusive.

As generally used herein, n1 is an integer of 1 to 5, inclusive. Incertain embodiments, n1 is 1. In certain embodiments, n2 is 2. Incertain embodiments, n3 is 3. In certain embodiments, n4 is 4. Incertain embodiments, n5 is 5.

In certain embodiments, n1 is 1 and Ring A is one of the formulae:

In certain embodiments, n1 is 2, and Ring A is one of the formulae:

In certain embodiments, n1 is 3 and Ring A is one of the formulae:

In certain embodiments, n1 is 4, and Ring A is one of the formulae:

In certain embodiments, n1 is 5, and Ring A is of the formula:

In certain embodiments, Ring A is

wherein R^(RA) is one of the following formulae:

wherein R^(A1), R^(A2), and R^(AN) are as defined herein.

In certain embodiments, Ring A is one of the formulae:

wherein each instance of R^(RA) is independently hydrogen, —CN, —CH₃,—OCH₃, —NHAc, —NHC(═O)Ph, —NHSO₂CH₃, or —C(═O)NH₂.

In certain embodiments, Ring A is one of the following formulae:

As generally defined herein, R^(RA) is independently hydrogen, halogen,optionally substituted. C₁₋₆alkyl, optionally substituted acyl, —CN,—OR^(AO), or —N(R^(AN))₂. In certain embodiments, R^(RA) is hydrogen. Incertain embodiments, R^(RA) is halogen. In certain embodiments, R^(RA)is —F, —Cl, —Br, or —I. In certain embodiments, R^(RA) is —CN. Incertain embodiments, R^(RA) is optionally substituted C₁₋₆ alkyl. Incertain embodiments, R^(RA) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(RA) is methyl, ethyl, n-propyl, or iso-propyl. Incertain embodiments, R^(A) is substituted C₁₋₆ alkyl. In certainembodiments, R^(RA) is —CF₃, —CHF₂, or —CH₂F. In certain embodiments,R^(RA) is optionally substituted acyl. In certain embodiments, R^(RA) isacetyl. In certain embodiments, R^(RA) is —C(═O)NH₂.

In certain embodiments, R^(RA) is —OR^(AO), wherein each instance ofR^(AO) is independently hydrogen, optionally substituted alkyl,optionally substituted carbocyclyl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted heteroaryl,or an oxygen protecting group. In certain embodiments, R^(RA) is —OH. Insome embodiments, R^(RA) is —OR^(AO), wherein R^(AO) is independentlyoptionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆carbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, or an oxygen protectinggroup. In certain embodiments, R^(RA) is —OR^(AO), wherein R^(AO) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, RR is—OR^(AO), wherein R^(AO) is unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(RA) is —O-methyl, —O-ethyl, —O-propyl, or —O-isopropyl.In certain embodiments, R^(RA) is —OR^(AO), wherein R^(AO) is optionallysubstituted heterocyclyl. In certain embodiments, R^(RA) is —OR^(AO),wherein R^(AO) is optionally substituted aryl. In certain embodiments,R^(RA) is —O-phenyl. In certain embodiments, R^(RA) is —OR^(AO), whereinR^(AO) is optionally substituted heteroaryl. In certain embodiments,R^(RA) is —OR^(AO), wherein R^(AO) is an oxygen protecting group. Incertain embodiments, R^(RA) is —OR^(AO), wherein R^(AO) is Ac, Boc, TBS,TIPS, Bn, or Bz.

In certain embodiments, R^(RA) is

wherein each instance of R^(RA2) is independently optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted phenyl, optionally substituted five- or six-memberedheterocyclyl, or optionally substituted heteroaryl. In certainembodiments, R^(RA) is —OBn.

In certain embodiments, R^(RA) is —N(R^(AN))₂, each instance of R^(AN)is independently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted acyl, or a nitrogen protecting group. In certainembodiments, R^(RA) is —N(R^(AN))₂, wherein each instance of R^(AN) isindependently hydrogen, optionally substituted alkyl, optionallysubstituted acyl, or a nitrogen protecting group. In certainembodiments, R^(RA) is —NH₂. In some embodiments, R^(RA) is —N(R^(AN))₂.In certain embodiments, R^(RA) is —NHR^(AN), wherein R^(AN) isoptionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted acyl, or anitrogen protecting group. In certain embodiments, R^(RA) is —NHR^(AN),wherein R^(AN) is optionally substituted C₁₋₆ alkyl. In certainembodiments, R^(RA) is —NHR^(AN), wherein R^(AN) is unsubstituted C₁₋₆alkyl. In certain embodiments, R^(RA) is —NH-methyl, —NH-ethyl,—NH-n-propyl, or —NH-iso-propyl. In certain embodiments, R^(RA) is—NHR^(AN), wherein R^(AN) is a nitrogen protecting group. In certainembodiments, R^(RA) is —NHSO₂CH₃.

In certain embodiments, R^(RA) is optionally substituted C₃₋₆carbocyclyl. In certain embodiments, R^(RA) is optionally substitutedaryl. In certain embodiments, R^(RA) is optionally substituted phenyl.In certain embodiments, R^(RA) is phenyl. In certain embodiments, R^(RA)is substituted phenyl. In certain embodiments, R^(RA) is o-CH₃-Ph,m-CH₃-Ph, p-CH₃-Ph, o-C₂H₅-Ph, m-C₂H₅-Ph, p-C₂H₅-Ph, o-^(i)Pr-Ph,m-^(i)Pr-Ph, p-^(i)Pr-Ph, o-Cl-Ph, m-Cl-Ph, p-Cl-Ph, o-CF₃-Ph, m-CF₃-Ph,p-CF₃-Ph, o-Ph-Ph, m-Ph-Ph, p-Ph-Ph, o-NH₂-Ph, m-NH₂-Ph, p-NH₂-Ph,o-CH₃-m-NH₂-Ph, o-Cl-m-CF₃-Ph, or

In certain embodiments, R^(RA) is optionally substituted five- orsix-membered heterocyclyl. In certain embodiments, R^(RA) is optionallysubstituted five-membered heterocyclyl. In certain embodiments, R^(RA)is optionally substituted six-membered heterocyclyl. In certainembodiments, R^(RA) is optionally substituted five- or six-memberedheteroaryl. In certain embodiments, R^(RA) is optionally substitutedfive-membered heteroaryl. In certain embodiments, R^(RA) is optionallysubstituted six-membered heteroaryl. In certain embodiments, R^(RA) isthiazole, pyridine, or pyrimidine. In certain embodiments, R^(RA) iso-CH₃-pyridine, m-CH₃-pyridine, or p-CH₃-pyridine. In certainembodiments, R^(RA) is —N(R^(AN))₂, wherein each R^(AN) is independentlyoptionally substituted C₁₋₆ alkyl. In certain embodiments, R^(RA) is—N(R^(AN))₂, wherein each R^(AN) is independently unsubstituted C₁₋₆alkyl. In certain embodiments, R^(RA) is —N(CH₃)R^(AN), wherein eachR^(AN) is independently optionally substituted C₁₋₆ alkyl or a nitrogenprotecting group. In certain embodiments, R^(RA) is —N(R^(AN))₂, whereineach instance R^(AN) is independently selected from the group consistingof methyl, ethyl, or isopropyl. In some embodiments, R^(RA) is—N(R^(AN))₂, wherein each R^(AN) is the same. In some embodiments,R^(RA) is —N(R^(AN))₂, wherein each R^(AN) is different. In certainembodiments, R^(AN) is a nitrogen protecting group. In certainembodiments, R^(AN) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, or Ts.

In certain embodiments, R^(RA) is of the formula

wherein R^(RA1) is independently optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ carbocyclyl, optionally substituted phenyl,optionally substituted five- or six-membered heterocyclyl, optionallysubstituted five- or six-membered heteroaryl, —OR^(A), or —N(R^(B))₂. Incertain embodiments, R^(RA1) is independently optionally substitutedC₁₋₆ alkyl. In certain embodiments, R^(RA1) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(RA1) is methyl, ethyl, n-propyl, oriso-propyl. In certain embodiments, R^(RA) is substituted C₁₋₆ alkyl. Incertain embodiments, R^(RA1) is —CH₂Cl, —CHCl₂, —CHF₂, —CH₂F, or —CF₃.In certain embodiments, R^(RA1) is optionally substituted C₃₋₆carbocyclyl. In certain embodiments, R^(RA1) is optionally substitutedphenyl. In certain embodiments, R^(RA1) is phenyl. In certainembodiments, R^(RA1) is substituted phenyl. In certain embodiments,R^(RA1) is o-CH₃-Ph, m-CH₃-Ph, p-CH₃-Ph, o-Cl-Ph, m-Cl-Ph, p-Cl-Ph, oro-Cl-m-CF₃-Ph. In certain embodiments, R^(RA1) is optionally substitutedfive- or six-membered heterocyclyl. In certain embodiments, R^(RA1) isoptionally substituted five-membered heterocyclyl. In certainembodiments, R^(RA1) is optionally substituted six-memberedheterocyclyl. In certain embodiments, R^(RA1) is optionally substitutedfive- or six-membered heteroaryl. In certain embodiments, R^(RA1) isoptionally substituted five-membered heteroaryl. In certain embodiments,R^(RA1) is optionally substituted six-membered heteroaryl. In certainembodiments, R^(RA1) is optionally substituted pyridine. In certainembodiments, R^(RA1) is pyridine.

In certain embodiments, R^(RA) is of the formula

wherein each instance of R^(RA2) is independently optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted phenyl, optionally substituted five- or six-memberedheterocyclyl, or optionally substituted five- or six-memberedheterocyclyl. In certain embodiments, R^(RA2) is independentlyoptionally substituted C₁₋₆ alkyl. In certain embodiments, R^(RA2) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(RA2) is methyl,ethyl, n-propyl, or iso-propyl. In certain embodiments, R^(RA2) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(RA2) is —CH₂Cl,—CHCl₂, —CHF₂, —CH₂F, or —CF₃. In certain embodiments, R^(RA2) isoptionally substituted C₃₋₆ carbocyclyl. In certain embodiments, R^(RA2)is optionally substituted phenyl. In certain embodiments, R^(RA2) isphenyl. In certain embodiments, R^(RA2) is substituted phenyl. Incertain embodiments, R^(RA2) is one the formulae: o-CH₃-Ph, m-CH₃-Ph,p-CH₃-Ph, o-Cl-Ph, m-Cl-Ph, orp-Cl-Ph.

In certain embodiments, R^(RA) is hydrogen, or one of the followingformulae:

—CN, —Cl, —CF₃, —CH₃, -Ph, —OH, —OCH₃, —OPh, —NH₂, —NHAc, —NHSO₂CH₃,

In certain embodiments, Ring A is optionally substituted five-memberedheteroaryl with two heteroatoms selected from the group consisting of O,S, and N. In certain embodiments, Ring A is one of the followingformulae:

wherein R^(RA) is as defined herein, a indicates the point of attachmentto the alkyne; and each instance of n2 is independently an integer of 1or 2. In certain embodiments, R^(RA) is one of the following formulae:

wherein R^(RA1), R^(RA2), and R^(AN) are as defined herein.

In certain embodiments, n2 is 1. In certain embodiments, n2 is 2.

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is optionally substituted six-memberedheteroaryl with one or two N. In certain embodiments, Ring A is one ofthe following formulae:

wherein R^(RA) is as defined herein, a indicates the point of attachmentto the alkyne; and each instance of n3 is independently an integer of 1to 4, inclusive. In certain embodiments, R^(RA) is one of the followingformulae:

wherein R^(RA1), R^(RA2), and R^(AN) are as defined herein.

As generally used herein, each instance of n3 is independently aninteger of 1 to 4, inclusive. In certain embodiments, n3 is 1. Incertain embodiments, n3 is 2. In certain embodiments, n3 is 3. Incertain embodiments, n3 is 4.

In certain embodiments of Ring A being an optionally substitutedpyridine, R^(RA) is one of the following formulae:

-   -   Hydrogen, -Ph, —OH, —NH₂, —OCH₃, —OPh, —Cl, —CF₃, —CH₃,

In certain embodiments, Ring A is optionally substituted 5,6-bicyclicheteroaryl with one, two, or three N. In certain embodiments, Ring A isone of the following formulae:

wherein R^(RA) is as defined herein; a indicates the point of attachmentto the alkyne; each instance of n4 is independently an integer of 1 to5, inclusive. In certain embodiments, R^(RA) is one of the followingformulae:

wherein R^(RA1), R^(RA2), and R^(AN) are as defined herein.

As generally used herein, each instance of n4 is independently aninteger of 1 to 4, inclusive. In certain embodiments, n4 is 1. Incertain embodiments, n4 is 2. In certain embodiments, n4 is 3. Incertain embodiments, n4 is 4. In certain embodiments, n4 is 5.

In certain embodiments, when Ring A is optionally substituted5,6-bicyclic heteroaryl with one, two, or three N atoms, each instanceof R^(RA) is selected from the group consisting of —F, —CF₃, —CN, and—NHAc.

In certain embodiments, Ring A is one of the following formulae:

In some embodiments, a compound of the present invention is of one ofthe following formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a provided compound is of one of the followingformulae:

or a pharmaceutically acceptable salt thereof,

R^(pa) is hydrogen, halogen, CN, optionally substituted C₁₋₆ alkyl,—OR^(A), —N(R^(B))₂, —NH—CO—R^(C);

R^(C) is optionally substituted C₁₋₆ alkyl;

R^(pb) is independently hydrogen, halogen, CN, —OR^(A), —N(R^(B))₂,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆carbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl;

each of R^(pc) and R^(pd) is independently hydrogen, halogen, CN,—OR^(A), or optionally substituted C₁₋₆ alkyl;

or R^(pc) and R^(pd) are joined to form ═O; and

R^(pe) is optionally substituted six-membered heterocyclyl, —OR^(A), or—N(R^(B))₂; and

each instance of R^(A) is independently hydrogen, optionally substitutedC₁₋₆alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, or an oxygen protecting group; and

each instance of R^(B) is independently hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heteraryl, optionally substituted acyl, or a nitrogenprotecting group.

In certain embodiments, a compound of the present invention is ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹ and Ring A areas defined herein.

In certain embodiments, a compound of the present invention is ofFormula (III):

or a pharmaceutically acceptable salt thereof, wherein Ring A, R^(1a)and m1 are as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (III-i):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (III-a):

or a pharmaceutically acceptable salt thereof, wherein Ring A and R^(1d)are as define herein.

In certain embodiments, a compound of the present invention is ofFormula (III-b):

or a pharmaceutically acceptable salt thereof, wherein Z is —O— or—NR^(NZ)—; and each instance of R^(NZ) is independently hydrogen,optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group; andRing A is as defined herein. In certain embodiments, Z is —O—. Incertain embodiments, Z is —NR^(NZ)—; and each instance of R^(NZ) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group. In certain embodiments, Z is —NH—, —NCH₃—, or —NC₂H₅—.

In certain embodiments, a compound of the present invention is ofFormula (IV):

or a pharmaceutically acceptable salt thereof, wherein Ring A and R¹ areas defined herein.

In certain embodiments, a compound of the present invention is ofFormula (V):

or a pharmaceutically acceptable salt thereof, wherein Ring A, R^(1a)and m1 are as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (V-i):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (V-a):

or a pharmaceutically acceptable salt thereof, wherein Ring A and R^(1d)are as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (V-b):

or a pharmaceutically acceptable salt thereof, wherein Ring A is asdefined herein; and Z is —O— or —NR^(NZ)—; each instance of R^(NZ) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group. In certain embodiments, Z is —O—. In certainembodiments, Z is —NR^(NZ)—; and each instance of R^(NZ) isindependently hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group. In certain embodiments, Z is —NH—, —NCH₃—, or —NC₂H₅—.

In certain embodiments, a compound of the present invention is ofFormula (VI):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (VII):

or a pharmaceutically acceptable salt thereof, wherein R^(1a), m1; andRing A are as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (VII-i):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (VII-a):

or a pharmaceutically acceptable salt thereof, wherein R^(1d) and Ring Aare as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (VII-b):

or a pharmaceutically acceptable salt thereof, wherein Ring A is asdefined herein; Z is —O— or —NR^(NZ)—; and R^(NZ) is hydrogen,optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group. Incertain embodiments, Z is —O—. In certain embodiments, Z is —NR^(NZ)—;and R^(NZ) is hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group. In certain embodiments, Z is —NH—, —NCH₃—, or —NC₂H₅—.

In certain embodiments, a compound of the present invention is ofFormula (VIII):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (IX):

or a pharmaceutically acceptable salt thereof, wherein R^(1a), m1, andRing A are as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (IX-i):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the present invention is ofFormula (IX-a):

or a pharmaceutically acceptable salt thereof, wherein R^(1d) and Ring Aare as defined herein.

In certain embodiments, a compound of the present invention is ofFormula (IX-b):

or a pharmaceutically acceptable salt thereof, wherein Ring A is asdefined herein; Z is —O— or —NR^(NZ)—; and R^(NZ) is hydrogen,optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group. Incertain embodiments, Z is —O—. In certain embodiments, Z is —NR^(NZ)—;and R^(NZ) is hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group. In certain embodiments, Z is —NH—, —NCH₃—, or —NC₂H₅—.

As used in any one of Formulae (I)-(IX), in certain embodiments, R^(pa)is hydrogen. In certain embodiments, R^(pa) is halogen. In certainembodiments, R^(pa) is F. In certain embodiments, R^(pa) is Cl. Incertain embodiments, R^(pa) is optionally substituted C₁₋₆ alkyl. Incertain embodiments, R^(pa) is unsubstituted C₁₋₆ alkyl (e.g. methyl).In certain embodiments, R^(pa) is —OR^(A) and R^(A) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pa) is —N(R^(B))₂ andeach instance of R^(B) is independently hydrogen or optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pa) is —NH₂. Incertain embodiments, R^(pa) is —NHR^(B) and R^(B) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pa) is —N(R^(B))₂ andeach instance of R^(B) is independently optionally substituted C₁₋₆alkyl. In certain embodiments, R^(pa) is NH—CO—R^(C) and R^(C) isoptionally substituted C₁₋₆ alkyl.

As used in any one of Formulae (I)-(IX), in certain embodiments, R^(pb)is hydrogen. In certain embodiments, R^(pb) is halogen. In certainembodiments, R^(pb) is F. In certain embodiments, R^(pb) is Cl. Incertain embodiments, R^(pb) is optionally substituted C₁₋₆ alkyl. Incertain embodiments, R^(pb) is unsubstituted C₁₋₆ alkyl (e.g. methyl).In certain embodiments, R^(pb) is —OR^(A) and R^(A) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pb) is —N(R^(B))₂ andeach instance of R^(B) is independently hydrogen or optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pb) is —NH₂. Incertain embodiments, R^(pb) is —NHR^(B) and R^(B) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, R^(pb) is —N(R^(B))₂ andeach instance of R^(B) is independently optionally substituted C₁₋₆alkyl. In certain embodiments, R^(pb) is optionally substituted C₃₋₆carbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl. In certainembodiments, R^(pb) is optionally substituted five- or six-memberedcarbocyclyl, optionally substituted five- or six-membered aryl,optionally substituted five- or six-membered heterocyclyl, or optionallysubstituted five- or six-membered heteroaryl.

As used in any one of Formulae (I)-(IX), in certain embodiments, R^(pc)is hydrogen. In certain embodiments, R^(pd) is hydrogen. In certainembodiments, R^(pc) and R^(pd) are hydrogen. In certain embodiments,R^(pc) and R^(pd) are joined to form ═O.

As used in any one of Formulae (I)-(IX), in certain embodiments, R^(pe)is optionally substituted six-membered heterocyclyl. In certainembodiments, R^(pe) is —OR^(A), and and R^(A) is optionally substituted.C₁₋₆alkyl. In certain embodiments, R^(pe) is —N(R^(B))₂ and eachinstance of R^(B) is independently hydrogen or optionally substitutedC₁₋₆ alkyl. In certain embodiments, R^(pe) is —NH₂. In certainembodiments, R^(pe) is —NHR^(B) and R^(B) is optionally substituted C₁₋₆alkyl. In certain embodiments, R^(pe) is —N(R^(B))₂ and each instance ofR^(B) is independently optionally substituted C₁₋₆ alkyl.

In some embodiments, a provided compound is one of the compounds inTable 1.

TABLE 1 Exemplary compounds Structure Example#

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

Enzymatic assays have shown that compounds as described herein areinhibitors of MNK1 and MNK2 with IC₅₀ values in the range of less thanapproximately 500 nM. eIF4e phosphorylation inhibition in Hela cell linewas found to have IC₅₀s in average up to 10 times higher than theenzymatic IC₅₀s. These cell-based IC₅₀s vary from as low asapproximately 5 μM or lower.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable form thereof (e.g., apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof), and, optionally, a pharmaceutically acceptableexcipient.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising an inventive compound, and optionally apharmaceutically acceptable excipient, and to their use for treatingdiseases associated with aberrant MNK1 or MNK2 activity or dysregulationof the MNK1 or MNK2 pathway, where MNK1 and MNK2 play a role (MNKoverexpression, eIF4E overexpression, P38 MAPK kinase pathway).Exemplary MNK-related disorders include, but are not limited to,metabolic diseases such as obesity, as well as related disorders such aseating disorder, cachexia, diabetes mellitus, hypertension, coronaryheart disease, hypercholesterolemia, dyslipidemia, osteoarthritis,gallstones, and sleep apnea, neurodegenerative disorders such asAlzheimer's disease, and cancer such as breast, prostate, hematologicalmalignancies (e.g., CML, AML), head and neck, colon, bladder, prostaticadenocarcinoma, lung, cervical, and lymphomas.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for thepreparation of a medicament for the prophylaxis and treatment of aPI3-kinase (PI3K) related disorder. In certain embodiments, thePI3K-related disorder is PI3K α-related disorder. In certainembodiments, the PI3K-related disorder is PI3K β-related disorder. Incertain embodiments, the PI3K-related disorder is PI3K γ-relateddisorder. In certain embodiments, the PI3K-related disorder is PI3Kδ-related disorder. Exemplary PI3K-related disorders include, but arenot limited to, cancers such as ovarian cancer, cervical cancer, breastcancer, colon cancer, rectal cancer, endometrial cancer, stomach cancer,liver cancer, lung cancer, thyroid cancer, acute myelogenous leukemia(AML), chronic myelogenous leukemia (CML), and glioblastomas.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for thepreparation of a medicament for the prophylaxis and treatment of a Januskinase (JAK) related disorder. In certain embodiments, the JAK-relateddisorder is JAK1-related disorder. In certain embodiments, theJAK-related disorder is JAK2-related disorder. In certain embodiments,the JAK-related disorder is JAK3-related disorder. Exemplary JAK-relateddisorders include, but are not limited to, psoriasis, rheumatoidarthritis, and cancers such as prostate, colon, ovarian and breastcancers, melanoma, leukemia and other haematopoietic malignancies.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for theprophylaxis and treatment of a Human Epidermal Growth FactorReceptor-related (HER-) disorder. In certain embodiments, theHER-related disorder is HER2-related disorder. In certain embodiments,the HER-related disorder is HER3-related disorder. Exemplary HER-relateddisorders include, but are not limited to, cancers such as breast, lung,kidney, brain, ovarian, colon, cervical, endometrial, prostate, liver,thyroid, GI tract, blood and lymphoma and other diseases such asmultiple sclerosis.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising these compounds and to their use for thepreparation of a medicament for the prophylaxis and treatment of amTOR-related disorder. Exemplary mTOR-related disorders include, but arenot limited to, cancers such as breast, lung, kidney, brain, ovarian,colon, cervical, endometrial, prostate, liver, thyroid, GI tract, bloodand lymphoma and other diseases such as hamartoma syndromes, rheumatoidarthritis, multiple sclerosis.

In certain embodiments, the kinase-related condition (e.g., MNK1- and/orMNK2-related condition) is selected from the group consisting ofproliferative diseases, neurodegenerative diseases, autoimmune diseases,and inflammatory diseases.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations informulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrierand/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate(Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitanmonooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylenemonostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.,CREMOPHOR®), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether(Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68,Poloxamer P188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, etc. and/or combinationsthereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, andcombinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as CREMOPHOR,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquids to the dermis via a liquid jetinjector and/or via a needle which pierces the stratum corneum andproduces a jet which reaches the dermis are suitable. Jet injectiondevices are described, for example, in U.S. Pat. Nos. 5,480,381;5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; andPCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particledelivery devices which use compressed gas to accelerate vaccine inpowder form through the outer layers of the skin to the dermis aresuitable. Alternatively or additionally, conventional syringes can beused in the classical mantoux method of intradermal administration,

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered. by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) and as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier. Such drops may furthercomprise buffering agents, salts, and/or one or more other of theadditional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Still further encompassed by the invention are kits (e.g.,pharmaceutical packs). The kits provided may comprise an inventivepharmaceutical composition or compound and a container (e.g., a vial,ampule, bottle, syringe, and/or dispenser package, or other suitablecontainer). In some embodiments, provided kits may optionally furtherinclude a second container comprising a pharmaceutical excipient fordilution or suspension of an inventive pharmaceutical composition orcompound. In some embodiments, the inventive pharmaceutical compositionor compound provided in the container and the second container arecombined to form one unit dosage form.

Optionally, a single container may comprise one or more compartments forcontaining an inventive pharmaceutical composition or compound, and/or apharmaceutically acceptable excipient for suspension or dilution. Insome embodiments, a single container can be appropriate for modificationsuch that the container may receive a physical modification so as toallow combination of compartments and/or components of individualcompartments. For example, a foil or plastic bag may comprise two ormore compartments separated by a perforated seal which can be broken soas to allow combination of contents of two individual compartments oncethe signal to break the seal is generated. A kit may thus comprise suchmulti-compartment containers providing an inventive pharmaceuticalcomposition or compound and one or more pharmaceutically acceptableexcipients.

Optionally, instructions for use are additionally provided in such kitsof the invention. Such instructions may provide, generally, for example,instructions for dosage and administration. In other embodiments,instructions may further provide additional detail relating tospecialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination with anadditional therapeutic agent.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease, disorder, or conditionbeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of the invention may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder, and/or it mayachieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. In will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

Exemplary additional therapeutically active agents include, but are notlimited to, small organic molecules such as drug compounds (e.g.,compounds approved by the U.S. Food and Drug Administration as providedin the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Insome embodiments, an additional therapeutically active agent is a kinaseinhibitor. In some embodiments, an additional therapeutically activeagent is an inhibitor of MAP kinase. In some embodiments, an additionaltherapeutically active agent is an inhibitor of JAK (e.g. JAK1, JAK2, orJAK3). In some embodiments, an additional therapeutically active agentis an inhibitor of PI3K (e.g. PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ). In someembodiments, an additional therapeutically active agent is an inhibitorof HER (e.g. HER2 or HER3 inhibitor). In some embodiments, an additionaltherapeutically active agent is an inhibitor of mTOR (e.g. mTORC1 ormTORC2). In some embodiments, an additional therapeutically active agentis a chemotherapeutic agent.

Also encompassed by the present disclosure are kits (e.g.,pharmaceutical packs). The kits provided may comprise a providedpharmaceutical composition or compound and a container (e.g., a vial,ampule, bottle, syringe, and/or dispenser package, or other suitablecontainer). In some embodiments, provided kits may optionally furtherinclude a second container comprising a pharmaceutical excipient fordilution or suspension of a provided pharmaceutical composition orcompound. In some embodiments, a provided pharmaceutical composition orcompound provided in the container and the second container are combinedto form one unit dosage form. In some embodiments, a provided kitsfurther includes instructions for use.

Methods of Treatment and Uses

Compounds and compositions described herein are generally useful for theinhibition of one or more kinases. In certain embodiments, compounds andcompositions described herein are generally useful for the inhibition ofMNK1 and/or MNK2. In some embodiments, methods of treatingkinase-related disorder in a subject are provided which compriseadministering an effective amount of a compound described herein (e.g.,a compound as described herein), or a pharmaceutically acceptable formthereof), to a subject in need of treatment. In some embodiments,methods of treating MNK1- and/or MNK2-related disorder in a subject areprovided which comprise administering an effective amount of a compounddescribed herein (e.g., a compound as described herein), or apharmaceutically acceptable form thereof), to a subject in need oftreatment. In certain embodiments, the effective amount is atherapeutically effective amount. In certain embodiments, the effectiveamount is a prophylactically effective amount. In certain embodiments,the subject is suffering from a MNK1-related disorder. In certainembodiments, the subject is susceptible to a MNK1-mediated disorder. Incertain embodiments, the subject is suffering from a MNK2-relateddisorder. In certain embodiments, the subject is susceptible to aMNK2-mediated disorder.

As used herein, the term “kinase-related disorder” (e.g., “MNK1- and/orMNK2-related disorder”) means any disease, disorder, or otherpathological condition in which a kinase (e.g., MNK1 and/or MNK2) isknown to play a role. In some embodiments, the present disclosurerelates to treating or lessening the severity of one or more diseases inwhich MNK1 and/or MNK2 is known to play a role. Exemplary MNK-relateddisorders include, but are not limited to, metabolic diseases such asobesity, as well as related disorders such as eating disorder, cachexia,diabetes mellitus, hypertension, coronary heart disease,hypercholesterolemia, dyslipidemia, osteoarthritis, gallstones, andsleep apnea, neurodegenerative disorders such as Alzheimer's disease,and cancer such as breast, prostate, hematological malignancies (e.g.,CML, AML), head and neck, colon, bladder, prostatic adenocarcinoma,lung, cervical, and lymphomas.

In certain embodiments, a provided compound is useful for treating aproliferative disease, e.g., cancer. In certain embodiments, a providedcompound is useful for treating solid tumor. In certain embodiments, aprovided compound is useful for treating hematological cancer. Exemplarycancers include, but are not limited to, acoustic neuroma;adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.,cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast); brain cancer (e.g., meningioma,glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma),medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma;craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer,colorectal adenocarcinoma); connective tissue cancer; epithelialcarcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g.,uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarinoma); Ewingsarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) e.g., polycythemia Vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer [e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)]; small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).In certain embodiments, a provided compound is useful for treatingbreast cancer, protate cancer, hematological malignancies (e.g., CML,AML), colon cancer, bladder cancer, prostatic adenocarcinoma, lungcancer, cervical cancer, and lymphomas.

In certain embodiments, a provided compound is useful for treating aneurodegenerative disease. Exemplary neurodegenerative diseases include,but are not limited to, autism, or autism spectrum disorders (e.g.Asperger syndrome or Mendelsohnn's Syndrome), Alzheimer's disease,Huntington's disease, progressive supranuclear palsy, corticobasaldegeneration, frontotemporal lobar degeneration, Pick's disease,Parkinson's disease, Lewy body disease, and amyotropic lateral sclerosis(ALS).

In certain embodiments, a provided compound is useful for treating anautoimmune disease. Exemplary autoimmune diseases include, but are notlimited to, rheumatoid arthritis, spondyloarthropathies, goutyarthritis, degenerative joint diseases such as osteoarthritis, systemiclupus erythematosus, Sjogren's syndrome, ankylosing spondylitis,undifferentiated spondylitis, Behcet's disease, haemolytic autoimmuneanaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis,acute painful shoulder, psoriatic arthritis, juvenile arthritis, asthma,atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skincondition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)),enuresis, eosinophilic disease, gastrointestinal disorder (e.g.,selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD)(e.g., Crohn's disease, ulcerative colitis, collagenous colitis,lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet'ssyndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)),Still's disease, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Grave's disease, acute disseminated encephalomyelitis,Addison's disease, opsoclonus-myoclonus syndrome, antiphospholipidantibody syndrome, autoimmune hepatitis, celiac disease, Goodpasture'ssyndrome, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, warm autoimmune hemolytic anemia, alopeciauniversalis, chronic fatigue, dysautonomia, neuromyotonia, vulvodyniaand disorders ameliorated by a gastroprokinetic agent (e.g., ileus,postoperative ileus and ileus during sepsis; gastroesophageal refluxdisease (GERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, a provided compound is useful for treating aninflammatory disease. The term “inflammatory disease” refers to thoseconditions that are characterized by signs of pain (dolor, from thegeneration of noxious substances and the stimulation of nerves), heat(calor, from vasodilatation), redness (rubor, from vasodilatation andincreased blood flow), swelling (tumor, from excessive inflow orrestricted outflow of fluid), and/or loss of function (functio laesa,which can be partial or complete, temporary or permanent. Inflammationtakes on many forms and includes, but is not limited to, acute,adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse,disseminated, exudative, fibrinous, fibrosing, focal, granulomatous,hyperplastic, hypertrophic, interstitial, metastatic, necrotic,obliterative, parenchymatous, plastic, productive, proliferous,pseudomembranous, purulent, sclerosing, seroplastic, serous, simple,specific, subacute, suppurative, toxic, traumatic, and/or ulcerativeinflammation.

Exemplary inflammatory diseases include, but are not limited toinflammation associated with acne, asthma, arteritis (e.g.,polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu'sarteritis), arthritis (e.g., crystalline arthritis, osteoarthritis,psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoidarthritis, and Reiter's arthritis), ankylosing spondylitis, amylosis,amyotrophic lateral sclerosis, autoimmune diseases, allergies orallergic reactions, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, Chagas disease, chronic obstructivepulmonary disease, cermatomyositis, dry eye syndrome, diverticulitis,diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus), askin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus(itch)), endometriosis, Guillain-Barre syndrome, infection, ischaemicheart disease, Kawasaki disease, glomerulonephritis, gingivitis,hypersensitivity, headaches (e.g., migraine headaches, tensionheadaches), ileus (e.g., postoperative ileus and ileus during sepsis),idiopathic thrombocytopenic purpura, interstitial cystitis (painfulbladder syndrome), gastrointestinal disorder (e.g., selected from pepticulcers, regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis),inflammatory bowel syndrome (IBS), lupus, multiple sclerosis, morphea,myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigusvulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primarybiliary cirrhosis, neuroinflammation associated with brain disorders(e.g., autism, or autism spectrum disorders (e.g. Asperger syndrome orMendelsohnn's Syndrome), Parkinson's disease, Huntington's disease, andAlzheimer's disease), prostatitis, chronic inflammation associated withcranial radiation injury, pelvic inflammatory disease, reperfusioninjury, regional enteritis, rheumatic fever, systemic lupuserythematosus, scleroderma, scleredoma, sarcoidosis,spondyloarthropathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis, prostatistis,appendicitis, Blau syndrome, blepharitis, bronchiolitis, cervicitis,cholangitis, cholecystitis, chronic recurrent multifocal osteomyelitis(CRMO), cryopyrin associated periodic syndrome (CAPS), dacryoadenitis,dermatomyositis, dry eye syndrome, encephalitis, endocarditis,endometritis, enterocolitis, epicondylitis, epididymitis, familialcold-induced autoinflammatory syndrome, familial Mediterranean fever(FMF), fasciitis, fibrositis, hepatitis, hidradenitis suppurativa,laryngitis, mastitis, meningitis, mevalonate kinase deficiency (MKD),Muckle-Well syndrome, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, inflammatory osteolysis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, pulmonaryfibrosis, pyelonephritis, pyoderma gangrenosum and acne syndrome (PAPA),pyogenic sterile arthritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, TNF receptor associated periodic syndrome(TRAPS), tonsillitis, undifferentiated arthropathy, uveitis, vaginitisand vulvitis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., inflammation resulting frominfection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds may also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia. The compounds may also be useful in treatinginflammation associated with cancer.

In certain embodiments, a provided compound is useful for treating orlessening the severity of arthropathies and osteopathological diseasesincluding, but not limited to, rheumatoid arthritis, osteoarthritis,gout, polyarthritis, and psoriatic arthritis.

In certain embodiments, a provided compound is useful for treating orlessening the severity of acute and chronic inflammatory diseasesincluding, but not limited to, ulcerative colitis, inflammatory boweldisease, Crohn's disease, dry eye syndrome, allergic rhinitis, allergicdermatitis, cystic fibrosis, chronic obstructive bronchitis, and asthma.

In certain embodiments, a provided compound is useful for treating orlessening the severity of hyperproliferative diseases including, but notlimited to, psoriasis or smooth muscle cell proliferation includingvascular proliferative disorders, atherosclerosis, and restenosis.

In certain embodiments, a provided compound is useful for treating orlessening the severity of endometriosis, uterine-fibroids, endometrialhyperplasia, and benign prostate hyperplasia.

In some embodiments, a provided compound is useful for treating orlessening the severity of one or more diseases and conditions, whereinthe disease or condition is selected from immune-related conditions ordiseases, which include, but are not limited to graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergies (e.g.,allergies to plant pollens, latex, drugs, foods, insect poisons, animalhair, animal dander, dust mites, or cockroach calyx), type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopicdermatitis.

In some embodiments, a provided compound is useful for treatingtumorogenesis.

In some embodiments, a provided compound is useful for treating ametabolic disorder (e.g., obesity, diabetes).

In some embodiments, the present disclosure provides a method ofinhibiting MNK1 comprising contacting MNK1 with an effective amount of acompound described herein (e.g., a compound as described herein), or apharmaceutically acceptable form thereof. In some embodiments, thepresent disclosure provides a method of inhibiting MNK2 comprisingcontacting MNK2 with an effective amount of a compound described herein(e.g., a compound as described herein), or a pharmaceutically acceptableform thereof. The MNK1 or MNK2 may be purified or crude, and may bepresent in a cell, tissue, or subject. Thus, such methods encompass bothinhibition of in vitro and in vivo MNK1 or MNK2 activity. In certainembodiments, the method is an in vitro method, e.g., such as an assaymethod. It will be understood by one of ordinary skill in the art thatinhibition of MNK1 or MNK2 does not necessarily require that all of theMNK1 or MNK2 be occupied by an inhibitor at once. Exemplary levels ofinhibition of MNK1 or MNK2 include at least 10% inhibition, about 10% toabout 25% inhibition, about 25% to about 50% inhibition, about 50% toabout 75% inhibition, at least 50% inhibition, at least 75% inhibition,about 80% inhibition, about 90% inhibition, and greater than 90%inhibition.

In some embodiments, provided is a method of inhibiting kinase activityin a subject in need thereof (e.g., a subject diagnosed as having akinase-related disorder) comprising administering to the subject aneffective amount of a compound described herein (e.g., a compound asdescribed herein), or a pharmaceutically acceptable form thereof, or apharmaceutical composition thereof. In some embodiments, provided is amethod of inhibiting MNK1 and/or MNK2 activity in a subject in needthereof (e.g., a subject diagnosed as having a MNK1- and/or MNK2-relateddisorder) comprising administering to the subject an effective amount ofa compound described herein, or a pharmaceutically acceptable formthereof, or a pharmaceutical composition thereof.

EXAMPLES

Compounds as described herein were synthesized and their ability toinhibit MNK1/2 kinase was evaluated both in enzymatic and in cell-basedassays. In parallel, their ability to inhibit other kinases was alsoassessed (Table 2). Enzymatic assays have shown that compounds asdescribed herein are inhibitors of MNK1 and MNK2 with IC₅₀ values lowerthan about 500 nM. eIF4e phosphorylation inhibition in Hela cell linewas found to have IC₅₀s in average 10 time higher than the enzymaticIC₅₀s. These cell-based IC₅₀s are less than about 5 μM.

TABLE 2 Enzymatic and Cellular IC₅₀ Activities of Exemplified CompoundsIC₅₀ (μM) Example # MNK1 MNK2 Hela 001 <0.5 <0.5 <5 002 <0.5 <0.5 <5 005<0.5 <0.5 <5 008 <0.5 <0.5 <5 010 <0.5 <0.5 <5 011 <0.5 <0.5 <5 013 <0.5<0.5 <5 016 <0.5 <0.5 <5 017 <0.5 <0.5 <5 019 <0.5 <0.5 <5 020 <0.5 <0.5<5 022 <0.5 <0.5 <5 023 <0.5 <0.5 <5 024 <0.5 <0.5 <5 027 <0.5 <0.5 <5028 <0.5 <0.5 <5 031 <0.5 <0.5 <5 032 <0.5 <0.5 <5 033 <0.5 <0.5 <5 034<0.5 <0.5 <5 035 <0.5 <0.5 <5 037 <0.5 <0.5 <5 040 <0.5 <0.5 <5 043 <0.5<0.5 <5 044 <0.5 <0.5 <5 045 <0.5 <0.5 <5 046 <0.5 <0.5 <5 047 <0.5 <0.5<5 048 <0.5 <0.5 <5 049 <0.5 <0.5 <5 051 <0.5 <0.5 <5 052 <0.5 <0.5 <5053 <0.5 <0.5 <5 054 <0.5 <0.5 <5 055 <0.5 <0.5 <5 056 <0.5 <0.5 <5 057<0.5 <0.5 <5 058 <0.5 <0.5 <5 059 <0.5 <0.5 <5 060 <0.5 <0.5 <5 063 <0.5<0.5 <5 064 <0.5 <0.5 <5 065 <0.5 <0.5 <5 070 <0.5 <0.5 <5 071 <0.5 <0.5<5 073 <0.5 <0.5 <5 074 <0.5 <0.5 <5 075 <0.5 <0.5 <5 089 <0.5 <0.5 <5094 <0.5 <0.5 <5 095 <0.5 <0.5 <5 096 <0.5 <0.5 <5 097 <0.5 <0.5 <5 098<0.5 <0.5 <5 099 <0.5 <0.5 <5 101 <0.5 <0.5 <5 102 <0.5 <0.5 <5 103 <0.5<0.5 <5 104 <0.5 <0.5 <5 105 <0.5 <0.5 <5 106 <0.5 <0.5 <5 107 <0.5 <0.5<5 108 <0.5 <0.5 <5 109 <0.5 <0.5 <5 110 <0.5 <0.5 <5 111 <0.5 <0.5 <5114 <0.5 <0.5 <5 115 <0.5 <0.5 <5 116 <0.5 <0.5 <5 121 <0.5 <0.5 <5 122<0.5 <0.5 <5 123 <0.5 <0.5 <5

SYNTHETIC EXAMPLES Abbreviations

-   CAN: acetonitrile-   AcOEt: ethyl acetate-   AcOH: acetic acid-   AUC: area under the curve-   Brine: saturated aqueous solution of NaCl-   cat.: catalyst-   d: day(s)-   DCM: dichloromethane-   DIPEA: diisopropyl-ethyl-amine-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   DMSO-d₆: per-deuterated dimethylsulfoxide-   dppf: 1,1′-Bis(diphenylphosphino) ferrocene-   EDCI: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide)-   Ether: diethylether-   EtOH: ethanol-   h: hour(s)-   HATU: 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HBTU:    O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate-   HOBt: N-Hydroxybenzotriazole-   HPLC: high pressure liquid chromatography-   L: liter(s)-   LC-MS: Liquid chromatography-mass spectrometry-   Me: methyl-   MeOH: methanol-   min: minute(s)-   m.p.: melting point-   MS: mass spectrometry-   NBS: N-Bromosuccinimide-   Et₃N: triethylamine-   NIS: N-iodosuccinimide-   NMM: N-methylmorpholine-   NMR: Nuclear Magnetic Resonance-   Pd(dppf)Cl₂:    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   THF: tetrahydrofuran-   TFA: trifluoroacetic acid-   TLC: thin layer chromatography-   TMS: trimethylsilyl    Synthesis of Intermediates

Intermediates 1: 4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoic Acid

Step 1: Preparation of ethyl 4-(imidazo[1,2-b]pyridazin-6-yl)benzoate: Amixture of 6-chloroimidazo[1,2-b]pyridazine (10 g, 65.34 mmol),4-Ethoxycarbonyl phenylboronic acid (13.94 g, 71.88 mmol), K₃PO₄ (27.7g, 130.68 mmol) in 1,4-dioxane (200 mL) and water (40 mL) was stirredunder Argon for 1 h. Pd(PPh₃)₄ (3.76 g, 3.26 mmol) was added and thereaction mixture was heated at 90° C. for 4 h. The reaction mixture wasdiluted with EtOAc (2×200 mL) and washed with water (2×100 mL) and brinesolution (2×100 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to obtain crude product. Thecrude product was purified by column chromatography (silica gel, eluentpetroleum ether/EtOAc 90:10 to 50:50) to afford ethyl4-(imidazo[1,2-b]pyridazin-6-yl)benzoate (5 g, 45%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.79 (s, 1H), 8.55 (s, 1H),7.78-7.72 (m, 2H), 7.67-7.46 (m, 3H), 6.94 (d, J=12.0 Hz, 2H), 4.03 (q,J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H); MS (ESI) m/z 268.1[C₁₆H₁₄N₂O₂+H]⁺.

Step 2: Preparation of ethyl4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoate: To a solution of ethyl4-(imidazo[1,2-b]pyridazin-6-yl)benzoate (5 g, 18.72 mmol) in DCM (50mL) and ACN (100 mL) was added NIS (5.04 g, 22.46 mmol) at 0° C. andstirred at room temperature for 3 h. The reaction mixture was filteredand washed with water to afford ethyl4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoate (7 g, 95%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.79 (s, 1H), 8.55 (s, 1H),7.78-7.72 (m, 2H), 7.67-7.46 (m, 2H), 6.94 (d, J=12.0 Hz, 2H), 4.03 (q,J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H); MS (ESI) m/z 393.1[C₁₆H₁₃IN₂O₂+H]⁺.

Step 3: Preparation of ethyl4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoate: Amixture of ethyl 4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoate (7 g,17.8 mmol), ethynyltrimethylsilane (2.99 mL, 21.36 mmol), Pd(PPh₃)₄ (1g, 0.89 mmol), CuI (507 mg, 2.67 mmol), and DIPEA (4.65 mL, 26.7 mmol)in 100 mL of DMF was stirred at 80° C. under N₂ for 4 h. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude residue was purified by flash column chromatography(silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford ethyl4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoate (5g, 78%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.20 (d,J=8.4 Hz, 2H), 8.12 (d, J=8.0 Hz, 2H), 8.11-8.03 (m, 2H), 7.60 (d, J=8.0Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.6 Hz, 3H); MS (ESI) m/z364.49 [C₂₀H₂₁N₃O₂Si+H]⁺.

Step 4: Preparation of 4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoicacid: To a solution of ethyl4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoate (5g, 13.77 mmol) in THF (50 mL) was added LiOH (1.15 g, 27.54 mmol) inwater (25 mL) and MeOH (20 mL) at room temperature and stirred for 5 h.The reaction mixture was concentrated under reduced pressure to afford4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoic acid (3.5 g, 96%, AUCHPLC 96.3%) as a light brown solid; m.p. 267-270° C.; ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 13.2 (s, 1H), 8.35 (d, J=10 Hz, 1H), 8.23 (d, J=8.4Hz, 2H), 8.18-8.11 (m, 3H), 8.01 (d, J=9.6 Hz, 1H), 5.03 (s, 1H); MS(ESI) m/z 264.25 [C₁₅H₉N₃O+H]⁺.

Intermediate 2: (4-(3-ethynylimidazo[1,2-b]pyridazin-6yl)phenyl)(morpholino)methanone

To a solution of 4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoic acid(1 g, 3.8 mmol) in DMF (10 mL) was added NMM (0.84 mL, 7.6 mmol)followed by HATU (2.16 g, 5.7 mmol) and the resulting mixture wasstirred at room temperature for 20 min. Morpholine (0.4 g, 4.56 mmol)was added and the reaction mixture stirred at room temperatureovernight, then diluted with EtOAc and washed in turn with water andbrine solution. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel, eluent CHCl₃/CH₃OH 97:3)to afford(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(1.0 g, 79%, LC-MS 99%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.10-8.03 (m, 4H), 7.59-7.57 (m, 3H), 3.79 (s, 1H), 3.66-3.49 (m,8H).

Intermediate 3:(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone

To a solution of 4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoic acid(816 mg, 3.10 mmol) in a mixture of DCM (6 mL) and DMF (6 mL) was addedsequentially N-methyl piperazine (2.06 mL, 18.61 mmol), HBTU (2.93 g,7.75 mmol), HOBt (795 mg, 5.89 mmol) and DIPEA (2.70 mL, 15.51 mmol),the resulting mixture was then stirred at room temperature for 12 h. Thereaction mixture was concentrated under reduced pressure then wasdiluted water (5 mL) and extracted with DCM (3×10 mL). The combinedextracts were dried over Na₂SO₄ filtered and concentrated to drynessunder reduced pressure. The residue was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(909 mg, 85%, AUC HPLC 95%) as light yellow foam. ¹H NMR (DMSO-d₆, 600MHz) δ (ppm): 8.31 (dd, J=0.9.5, 1.4 Hz, 1H), 8.21-8.09 (m, 3H), 7.96(d, J=9.6 Hz, 1H), 7.58 (d, J=7.9 Hz, 2H), 5.04-4.97 (m, 1H), 3.64 (s,2H), 2.47-2.22 (m, 4H), 2.20 (s, 3H); ¹³C NMR (DMSO-d₆, 150 MHz) δ(ppm): 168.3, 151.3, 139.0, 138.5, 137.6, 135.5, 127.6, 127.1, 126.4,117.7, 111.8, 90.8, 70.9, 54.6, 54.1 and 45.6; MS (ESI) m/z 346[C₂₀H₁₉N₅O+H]⁺.

Intermediate 4: 4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoic Acid

Step 1: Preparation of ethyl 4-(imidazo[1,2-a]pyridin-6-yl)benzoate:4-(ethoxycarbonyl)phenylboronic acid (7.09 g, 36.54 mmol), K₃PO₄ (19.37g, 91.36 mmol) and Pd(PPh₃)₄ (1.75 g, 1.52 mmol) were addedsequentially, under argon atmosphere, to a solution of6-bromoimidazo[1,2-a]pyridine (6 g, 30.45 mmol) in a mixture of1,4-dioxane (90 mL) and H₂O (10 mL). The reaction mixture was refluxedovernight and the reaction mixture was diluted with EtOAc and washed inturn with water and brine. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel, eluent petroleumether/EtOAc 1:1) to afford ethyl 4-(imidazo[1,2-a]pyridin-6-yl)benzoate(6.4 g, 79%, LC-MS 86.5%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.37 (s, 1H), 8.12 (d, J=7.9 Hz, 2H), 7.72-7.62 (m, 5H), 7.41 (d, J=9.3Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H); MS (ESI) m/z267.09 [C₁₆H₁₄N₂O₂+H]⁺.

Step 2: Preparation of ethyl4-(3-iodoimidazo[1,2-a]pyridin-6-yl)benzoate: To a solution of ethyl4-(imidazo[1,2-a]pyridin-6-yl)benzoate (6.4 g, 24.06 mmol) in ACN (50mL) was added NIS (6.49 g, 28.87 mmol) at 0° C. to room temperature andstirred at the same temperature for 3 h. TLC indicated absence ofstarting material and water (2×50 mL) was added to the reaction mixture.The reaction mixture was filtered and washed with water to afford ethyl4-(3-iodoimidazo[1,2-a]pyridin-6-yl)benzoate (8.5 g, 90%, LC-MS 99.5%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.50 (s, 1H), 8.01(d, J=8.4 Hz, 2H), 7.95-7.92 (m, 2H), 7.74-7.72 (m, 3H), 4.31 (q, J=7.0Hz, 2H), 1.32 (t, J=7.4 Hz, 3H); MS (ESI) m/z 392.5 [C₁₆H₁₃IN₂O₂+H]⁺.

Step 3: Preparation of ethyl4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoate: To asolution of ethyl 4-(3-iodoimidazo[1,2-a]pyridin-6-yl)benzoate (6 g,15.30 mmol) in DMF (50 mL) was added ethynyltrimethylsilane (2.57 mL,18.36 mmol), CuI (860 mg, 4.81 mmol), and DIPEA (4.22 mL, 22.95 mmol)under argon. Pd(PPh₃)₄ (883 mg, 0.76 mmol) was added and the reactionmixture was heated at 80° C. for 4 h. The reaction mixture was dilutedwith water (2×100 mL) which triggered a precipitate formation which wasfiltered to give crude product. The crude product was purified by flashchromatography (silica gel, eluent petroleum ether/EtOAc 1:1) to affordethyl 4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoate(54.5%, LC-MS 98%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.56(s, 1H), 8.10-8.02 (m, 3H), 7.91 (d, J=8.3 Hz, 2H), 7.81 (q, J=9.2 Hz,2H), 4.31 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H), 0.09 (s, 9H); MS(ESI) m/z 363.05 [C₂₁H₂₂N₂O₂Si+H].⁺

Step 4: Preparation of 4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoicacid: To a solution of ethyl4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoate (3 g,8.28 mmol) in THF (20 mL) was added LiOH (1.04 g, 24.86 mmol) in water(5 mL) at room temperature and stirred for 2 h. The reaction mixture wasconcentrated under reduced pressure to afford4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoic acid as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.02 (s, 1H), 8.64 (s, 1H), 8.02 (t, J=7.9Hz, 3H), 7.92 (d, J=8.4 Hz, 3H), 7.83 (s, 1H), 5.14 (s, 1H); MS (ESI)m/z 263 [C₁₆H₁₀N₂O₂+H]⁺.

Intermediate 5:(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

To a solution of 4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoic acid(600 mg, 2.28 mmol) in DMF (10 mL) was added NMM (0.5 mL, 4.58 mmol)followed by HATU (1.3 g, 3.43 mmol) and the reaction mixture was stirredfor 30 min. Morpholine (0.24 mL, 2.5 mmol) was added and stirred at roomtemperature for 16 h. The reaction mixture was diluted with EtOAc andwashed with water and brine solution. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel, eluentCHCl₃/CH₃OH 95:5) to afford(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(400 mg, 52.7%, LC-MS 96.7%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.47 (s, 1H), 7.92 (s, 1H), 7.72 (d, J=9.2 Hz, 2H), 7.61 (d,J=8.4 Hz, 2H), 7.54-7.52 (m, 2H), 5.12 (s, 1H), 3.86-3.84 (m, 8H); MS(ESI) m/z 332.09 [C₂₀H₁₇N₃O₂+H]⁺.

Intermediate 6: tert-butyl 4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate

To a solution of 4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoic acid(300 mg, 1.14 mmol) in DMF (10 mL) was added NMM (0.25 mL, 2.29 mmol)followed by HATU (652 mg, 1.71 mmol) at room temperature and stirred for30 min. To the reaction mixture, morpholine (234 mg, 1.25 mmol) wasadded and stirred at room temperature for overnight. The reactionmixture was diluted with EtOAc and washed with water and brine solution.The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel, eluent CHCl₃/CH₃OH 95:5) to afford tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(200 mg, 40.6%, LC-MS 99%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.47 (s, 1H), 7.93 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.61 (d, J=8.3 Hz,2H), 7.50 (d, J=7.9 Hz, 3H), 3.86-3.84 (m, 9H), 1.48 (s, 9H), 1.25 (s,2H); MS (ESI) m/z 431.10 [C₂₅H₂₆N₄O₃+H]⁺.

Intermediate 7: (4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino) Methanone

Step 1: To a solution of ethyl 4-(imidazo[1,2-a]pyrazin-6-yl)benzoate(8.00 g, 29.9 mmol) in DMF (200 mL), was added N-Iodosuccinimide (8.10g, 36.0 mmol) and the mixture was heated at 60° C. for 2 h and pouredonto ice water. The precipitate was isolated by filtration and dried toafford ethyl 4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)benzoate (11 g, 94%) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.80 (s, 1H),8.29 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 8.00 (s, 1H), 4.37-4.31(m, 2H), 1.34 (t, J=7.2 Hz, 3H); MS (ESI) m/z 393 [C₁₅H₁₂IN₃O₂]⁺.

Step 2: A solution of ethyl 4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)benzoate(11 g, 30.5 mmol) and LiOH.H₂O (5.00 g, 121 mmol) in THF/CH₃OH/H₂O(200/50/50 mL) was stirred for 12 h. The reaction mixture wasconcentrated, diluted with water (20 mL) and acidified with an aqueoussolution of HCl till pH 2, The precipitate was isolated by filtrationand dried to afford 4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)benzoic acid(8.00 g, 72%) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.12 (s,1H), 8.78 (s, 1H), 8.26 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.05(s, 1H); MS (ESI) m/z 366 [C₁₃H₈IN₃O₂+H]⁺.

Step 3: N-methyl-morpholine (3.0 mL, 7.5 mmol), HATU (7.5 g, 27 mmol)and morpholine (1.26 g, 14.85 mmol) were added sequentially to asolution of 4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)benzoic acid (5.0 g,3.25 mmol) in DMF (10 mL) and the resulting mixture was stirred at roomtemperature for 3 h under nitrogen atmosphere. The reaction mixture wasdiluted with water (50 mL) and the precipitate that has formed wasfiltered off and dried to afford(4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone (2.0g, 65%) as off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.50(s, 1H), 8.10 (d, 2H), 7.90 (s, 1H), 7.60 (d, 2H), 3.4-3.9 (m, 8H); MS(ESI) m/z 434 [C₁₇H₁₅N₄O₂+H]⁺.

Intermediate 8:(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone

Step 1: Preparation of 4-(imidazo[1,2-b]pyridazin-6-yl)benzoic acid

To a solution of 6-chloroimidazo[1,2-b]pyridazine (2 g, 13.07 mmol) in1, 4-dioxane (20 mL) and water (10 mL) were successively added4-boronobenzoic acid (2.58 g, 15.87 mmol), K₂CO₃ (3.6 g, 0.81 mmol), andPd(PPh₃)₄ (0.75 g, 6.5 mmol). The reaction mixture was heated at 100° C.for 15 h under argon. The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (3×20 mL). The combined organicphase was washed with brine (1×50 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to afford4-(imidazo[1,2-b]pyridazin-6-yl)benzoic acid (2 g, 64%) as a white solid(LC-MS 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (bs, 1H), 8.04 (s, 1H),8.3-8.01 (m, 5H), 7.85 (d, J=7.2 Hz, 2H); MS (ESI) m/z 240 [M+H]⁺.

Step 2: Preparation of 4-(3-iodoimidazo [1,2-b] pyridazin-6-yl) benzoicacid

A solution of 4-(imidazo[1,2-b]pyridazin-6-yl)benzoic acid (2 g, 84%purity, 7.02 mmol) and NIS (4.63 g, 20.77 mmol) in DMF (20 mL) washeated at 90° C. for 4 h. The reaction mixture was poured into ice-coldwater, the precipitate was isolated by filtration and dried to afford4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoic acid (1.5 g, 58%, HPLC93%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (bs, 1H),8.3-8.01 (m, 5H), 7.85 (d, J=7.2 Hz, 2H); MS (ESI) m/z 366 [M+H]⁺.

Step 3: Preparation of (4-(3-iodoimidazo [1,2-b] pyridazin-6-yl) phenyl)(4-methylpiperazin-1-yl) methanone

A solution of 4-(3-iodoimidazo [1,2-b] pyridazin-6-yl) benzoic acid (1.5g, 4.109 mmol), NMM (0.67 mL, 6.164 mmol) and HATU (3.12 g, 8.218 mmol)in DMF (20 mL) was stirred for 30 min. 1-methylpiperazine (0.546 mL,4.90 mmol) was added and the mixture was stirred at room temperature for6 h, then was diluted with EtOAc and washed with water and brinesolution. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The crude product was purifiedby column chromatography (silica gel, eluent CHCl₃/CH₃OH 90:10) to give(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(1.5 g, 82%, LC-MS 95%) as a yellow solid. MS (ESI) m/z: 448.06 [M+1].

Intermediate 9:(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

To a solution of 4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoic acid (4g, 10.95 mmol) in DMF (50 mL) was added NMM (2.21 mL, 21.91 mmol), HATU(8.32 g, 21.91 mmol) and the mixture was stirred for 30 min prior to theaddition of morpholine (1.14 mL, 13.14 mmol). The reaction mixture wasstirred for 16 h and was diluted with EtOAc and washed with water andbrine solution. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5) to afford(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (4.2g, 88%) as an off-white solid. MS (ESI) m/z 435 [M+1]⁺.

Example 1:(4-methylpiperazin-1-yl)(4-(3-(o-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

To a solution of(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(30 mg, 0.089 mmol), 1-iodo-2-methylbenzene (13.3 μL, 0.104 mmol) in amixture of THF and DMF (2:1, 1.5 mL) was added PdCl₂(PPh₃)₂ (3.0 mg,0.004 mmol), CuI (1.6 mg, 0.0086 mmol), Et₃N (1 mL) and then thereaction mixture was stirred at room temperature for 12 h. The reactionmixture was concentrated in vacuo to dryness and then purified by flashcolumn chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-methylpiperazin-1-yl)(4-(3-(o-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(20 mg, 53%, AUC HPLC 98%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.35 (d, J=9.4 Hz, 1H), 8.28-8.17 (m, 3H), 8.00 (d,J=9.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.41-7.33(m, 2H), 7.29 (td, J=7.2, 1.7 Hz, 1H), 3.84-3.56 (m, 3H), 2.72-2.51 (m,6H), 2.37 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.4, 151.3,139.5, 138.3, 137.3, 135.7, 131.1, 129.8, 129.1, 127.7, 127.1, 126.5,126.1, 121.6, 117.6, 112.5, 97.5, 80.5, 54.0, 53.7, 44.7, and 20.3; MS(ESI) m/z 436 [C₂₇H₂₅N₅O+H]⁺.

Example 2:(4-methylpiperazin-1-yl)(4-(3-(phenylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand iodobenzene in a similar method to that described for Example 1. Thereaction crude product was purified by flash column chromatography(silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-methylpiperazin-1-yl)(4-(3-(phenylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(18 mg, 50%, AUC HPLC 98%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.34 (d, J=9.4 Hz, 1H), 8.29-8.15 (m, 3H), 7.98 (d,J=9.4 Hz, 1H), 7.68-7.62 (m, 2H), 7.62-7.56 (m, 2H), 7.48 (dd, J=5.1,2.0 Hz, 3H), 3.68-3.65 (m, 2H), 2.48-2.32 (m, 4H), 2.26 (s, 3H); ¹³C NMR(150 MHz, DMSO-d₆) δ (ppm): 168.3, 151.3, 138.8, 137.5, 135.6, 131.2,129.3, 128.9, 127.7, 127.1, 126.4, 121.7, 117.6, 112.4, 98.4, 76.6,54.4, 54.0, 45.2; MS (ESI) m/z 422 [C₂₆H₂₃N₅O+H]⁺.

Example 3:(4-methylpiperazin-1-yl)(4-(3-(m-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand 1-iodo-3-methylbenzene in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-methylpiperazin-1-yl)(4-(3-(m-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(15 mg, 30%, AUC HPLC 98%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.34 (d, J=9.5 Hz, 1H), 8.24-8.16 (m, 3H), 7.98 (d,J=9.5 Hz, 1H), 7.64-7.56 (m, 2H), 7.50-7.41 (m, 2H), 7.37 (t, J=7.6 Hz,1H), 7.29 (ddt, J=7.9, 2.0, 0.9 Hz, 1H), 3.66-3.64 (m, 2H), 2.38-2.24(m, 7H), 2.20 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.3, 151.3,138.9, 138.7, 138.3, 137.6, 135.5, 131.6, 130.0, 128.8, 128.4, 127.7,127.2, 126.4, 121.5, 117.7, 112.3, 98.5, 76.2, 54.7, 54.2, 45.6, 20.7;MS (ESI) m/z 436 [C₂₇H₂₅N₅O+H]⁺.

Example 4:(4-methylpiperazin-1-yl)(4-(3-(p-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand 1-iodo-4-methylbenzene in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-methylpiperazin-1-yl)(4-(3-(p-tolylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(21 mg, 42%, AUC HPLC 98%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.33 (d, J=9.5 Hz, 1H), 8.28-8.12 (m, 3H), 7.97 (d,J=9.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.57-7.50 (m, 2H), 7.29 (d, J=7.8Hz, 2H), 3.67-3.59 (m, 2H), 2.41-2.22 (m, 7H), 2.20 (s, 3H); ¹³C NMR(150 MHz, DMSO-d₆) δ (ppm): 168.3, 151.3, 139.2, 138.6, 137.6, 135.6,131.2, 129.5, 127.7, 127.1, 126.4, 118.7, 117.6, 112.5, 98.5, 76.0,54.6, 54.2, 45.5, 21.1; MS (ESI) m/z 436 [C₂₇H₂₅N₅O+H]⁺.

Example 5:(4-methylpiperazin-1-yl)(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-methylpiperazin-1-yl)(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone and 4-iodopyridine in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-methylpiperazin-1-yl)(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(16 mg, 46%, AUC HPLC 97%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.67 (d, J=4.9 Hz, 2H), 8.35 (d, J=9.5 Hz, 1H), 8.28(s, 1H), 8.22 (d, J=8.0 Hz, 2H), 8.02 (d, J=9.5 Hz, 1H), 7.63 (d, J=8.0Hz, 2H), 7.60 (d, J=5.3 Hz, 2H), 3.82-3.69 (m, 2H), 2.87-2.60 (m, 4H),2.47 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.6, 151.6, 150.2,139.9, 139.5, 137.2, 135.7, 129.7, 128.0, 127.4, 126.7, 125.0, 118.4,111.5, 96.2, 81.1, 53.5, 44.2; MS (ESI) m/z 423 [C₂₅H₂₂N₆O+H]⁺.

Example 6:(4-(3-((4-methoxyphenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand 1-iodo-4-methoxybenzene in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-(3-((4-methoxyphenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(16 mg, 41%, AUC HPLC 97%) as a light brown solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.45-8.12 (m, 4H), 7.96 (d, J=7.4 Hz, 1H), 7.65-7.53(m, 4H), 7.03 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 3.74-3.56 (m, 2H),3.39-3.28 (m, 2H), 2.43-2.31 (m, 4H), 2.21 (s, 3H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.5, 160.0, 151.4, 137.6, 135.7, 133.1, 127.8,127.3, 127.2, 117.6, 114.7, 113.6, 110.8, 98.6, 55.4, 54.6, 54.1 and45.5; MS (ESI) m/z 452 [C₂₇H₂₅N₅O₂+H]⁺.

Example 7:N-(4-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand N-(4-iodophenyl)acetamide in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) to affordN-(4-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide(8 mg, 23%, AUC HPLC 99%) as a yellow solid; ¹H NMR (600 MHz, DMSO-d₆) δ(ppm): 10.22 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 8.25-8.15 (m, 3H), 7.97(d, J=9.5 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63-7.55 (m, 4H), 3.66-3.67(m, 2H), 2.44-2.25 (m, 4H), 2.08 (s, 3H), 2.08 (s, 3H); ¹³C NMR (150MHz, DMSO-d₆) δ (ppm): 168.7, 168.4, 151.3, 140.2, 138.7, 138.5, 135.6,132.1, 127.8, 127.2, 126.4, 119.0, 117.5, 115.7, 112.5, 99.5, 98.6,75.6, 54.2, 40.0, 24.1; MS (ESI) m/z 479 [C₂₈H₂₆N₆O₂+H]⁺.

Example 8: Preparation ofN-(3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanoneand N-(3-iodophenyl)acetamide in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordN-(3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide(15 mg, 43%, AUC HPLC 98%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 10.24 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 8.24-8.20 (m,3H), 8.05-7.91 (m, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.57 (dd, J=7.9, 2.0 Hz,1H), 7.40 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 3.74-3.59 (m, 4H),3.20-3.14 (m, 4H), 2.72 (s, 3H), 2.08 (s, 3H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 169.0, 168.7, 151.4, 139.8, 139.0, 138.8, 136.6,136.1, 128.1, 127.3, 126.6, 125.9, 122.0, 121.3, 119.9, 117.9, 112.3,98.6, 76.4, 52.4, 45.7, 24.2; MS (ESI) m/z 479 [C₂₈H₂₆N₆O₂+H]⁺.

Example 9:4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-iodobenzonitrile (51 mg, 0.225 mmol) in a similar method to thatdescribed for Example 1. The reaction crude product was purified byflash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 96:4) toafford4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile(50.5 mg, 77%, AUC HPLC 99%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.44-8.27 (m, 2H), 8.22 (d, J=8.2 Hz, 2H), 8.03 (d,J=9.1 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.63 (d,J=8.2 Hz, 2H), 3.71-3.51 (m, 6H), 3.41-3.33 (m, 2H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.5, 151.6, 139.8, 137.4, 135.6, 132.9, 131.9,128.0, 127.3, 126.7, 126.6, 118.5, 118.4, 111.3, 97.4, 80.8, 66.2, 45.8;MS (ESI) m/z 434 [C₂₆H₁₉N₅O₂+H]⁺.

Example 10:morpholino(4-(3-(pyridin-3-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-iodopyridine in a similar method to that described for Example 1.The reaction crude product was purified by flash column chromatography(silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordmorpholino(4-(3-(pyridin-3-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(10.0 mg, 16%, AUC HPLC 96%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.85 (s, 1H), 8.68-8.58 (m, 1H), 8.35 (d, J=9.5 Hz,1H), 8.26 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.08 (dt, J=7.9, 1.9 Hz, 1H),8.01 (d, J=9.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.54-7.51 (m, 1H),3.68-3.51 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.5, 151.5,151.4, 149.5, 139.3, 139.2, 138.6, 137.4, 135.6, 128.0, 127.3, 126.6,123.9, 119.0, 118.1, 111.9, 95.4, 79.7, 66.1, 47.7; MS (ESI) m/z 410[C₂₄H₁₉N₅O₂+H]⁺.

Example 11:N-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)methaneSulfonamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(3-iodophenyl)methanesulfonamide in a similar method to thatdescribed for Example 1. The reaction crude product was purified byflash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) toaffordN-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)methanesulfonamide (20.0 mg, 28%, AUC HPLC 97%) as a light yellow solid; ¹H NMR(600 MHz, DMSO-d₆) δ (ppm): 8.34 (d, J=9.5 Hz, 1H), 8.26-8.18 (m, 3H),7.99 (d, J=9.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.46-7.39 (m, 2H), 7.32(d, J=7.6 Hz, 1H), 7.25 (dd, J=8.1, 2.1 Hz, 1H), 3.71-3.55 (m, 8H), 3.01(s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.5, 151.4, 140.2, 139.0,138.8, 137.3, 135.7, 130.1, 128.0, 127.2, 126.5, 125.7, 122.5, 121.5,120.5, 117.8, 112.2, 98.4, 76.7, 66.1, 48.7, 47.7; MS (ESI) m/z 502[C₂₆H₂₃N₅O₄S+H]⁺.

Example 12:N-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)benzamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(3-iodophenyl)benzamide in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordN-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)benzamide(20.0 mg, 25%, AUC HPLC 97%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 10.43 (s, 1H), 8.34 (d, J=9.4 Hz, 1H), 8.30-8.13 (m,4H), 8.03-7.92 (m, 3H), 7.81 (dt, J=8.5, 1.3 Hz, 1H), 7.67-7.58 (m, 3H),7.58-7.51 (m, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.38 (dt, J=7.8, 1.3 Hz, 1H),3.69-3.52 (m, 4H), 3.37-3.22 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ(ppm): 168.6, 166.0, 151.4, 139.6, 138.8, 137.3, 135.7, 134.7, 131.9,129.5, 128.6, 128.0, 127.8, 127.2, 126.6, 126.4, 122.7, 122.0, 121.2,117.8, 98.6, 76.6, 66.1, 47.8; MS (ESI) m/z 528 [C₃₂H₂₅N₅O₃+H]⁺.

Example 13:N-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(3-iodophenyl)acetamide in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordN-(3-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)phenyl)acetamide(15.0 mg, 21%, AUC HPLC 99%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 10.15 (s, 1H), 8.33 (d, J=9.5 Hz, 1H), 8.27-8.16 (m,3H), 8.01-7.97 (m, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.55 (ddd, J=8.1, 2.2Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.31 (dt, J=7.6, 1.3 Hz, 1H), 3.68-3.54(m, 8H), 2.08 (s, 3H). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.9, 168.6,151.4, 139.7, 139.0, 138.8, 137.3, 135.7, 129.6, 128.0, 127.2, 126.5,125.8, 122.0, 121.3, 119.9, 117.8, 112.3, 98.6, 76.4, 66.2, 24.1; MS(ESI) m/z 466 [C₂₇H₂₃N₅O₃+H]⁺.

Example 14:(4-(3-((3-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-chloro-4-iodopyridine in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent EtOAc/CH₃OH 95:5) to afford(4-(3-((3-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(22.8 mg, 34.5%, AUC HPLC 96%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.26 (d, J=7.0 Hz, 4H), 8.13 (s, 2H), 7.84 (s, 2H),7.63 (d, J=7.7 Hz, 5H), 3.67 (s), 3.58 (s), 2.57 (s, 2H), 1.40-1.10 (m,4H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 179.9, 168.8, 152.1, 149.6,148.5, 137.9, 135.9, 129.5, 128.3, 127.6, 118.9, 93.9, 66.5, 48.0, 42.5,40.3, 40.2, 40.1, 39.9, 39.8, 39.6, 39.5, 29.9; MS (ESI) m/z 444[C₂₄H₁₈ClN₅O₂+H]⁺.

Example 15:(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 2-chloro-4-iodopyridine in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent EtOAc/CH₃OH 93:7) to afford(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(85 mg, 64%, AUC HPLC 96.0%) as a light brown solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.48 (d, J=4.8 Hz, 1H), 8.37-8.33 (m, 1H), 8.20 (d,J=7.8 Hz, 2H), 8.04-8.00 (m, 1H), 7.73 (s, 1H), 7.64-7.57 (m, 4H),3.39-3.31 (m, 4H); ¹³C-NMR (150 MHz, DMSO-d₆) δ (ppm): 168.9, 152.1,151.1, 150.7, 137.6, 135.7, 133.2, 128.2, 127.6, 127.0, 125.2, 124.6,122.3, 119.0, 95.4, 83.1, 66.3 and 46.5; MS (ESI) m/z 444[C₂₄H₁₈ClN₅O₂+H]⁺.

Example 16:(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) methanoneand 4-iodo-1H-pyrazolo[3,4-b]pyridine in a similar method to thatdescribed for Example 1. The reaction crude product was purified byflash column chromatography (silica gel, eluent EtOAc/CH₃OH 95:5) toafford(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(22.0 mg, 20.3%, AUC HPLC 97%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.59 (d, J=4.7 Hz, 1H), 8.38-8.35 (m, 2H), 8.32 (s,1H), 8.23 (d, J=7.8 Hz, 2H), 8.03 (d, J=9.5 Hz, 1H), 7.64 (d, J=7.9 Hz,2H), 7.41 (d, J=4.7 Hz, 1H), 3.68-3.38 (m, 8H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.7, 152.0, 149.3, 140.2, 139.8, 137.5, 135.8,132.2, 128.0, 127.4, 126.8, 122.9, 118.8, 118.2, 114.1, 111.6, 99.7,94.9, 84.5, 66.2 and 47.8; MS (ESI) m/z 450 [C₂₅H₁₉N₇O₂+H]⁺.

Example 17:(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) methanoneand 4-iodo-1H-pyrrolo[2,3-b]pyridin-6-amine in a similar method to thatdescribed for Example 1. The reaction crude product was purified byflash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) toafford(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(8 mg, AUC HPLC 95%) as a light yellow solid. ¹H NMR (600 MHz, DMSO-d₆)δ (ppm): 11.03 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 8.26 (s, 1H), 8.22 (d,J=6.0 Hz, 2H), 7.99 (d, J=6.0 Hz, 1H), 7.64 (d, J=6.0 Hz, 2H), 7.10 (d,J=6.0 Hz, 1H), 6.52 (s, 1H), 6.47 (d, J=6.0 Hz, 1H), 5.75 (s, 2H); ¹³CNMR (150 MHz, DMSO-d₆) δ (ppm): 169.1, 156.1, 152.1, 147.9, 139.6,137.6, 136.1, 128.3, 127.6, 126.8, 122.7, 121.9, 118.7, 112.6, 111.9,104.2, 99.6, 96.9, 80.7, 66.4, 63.3; MS (ESI) m/z 464 [C₂₆H₂₁N₇O₂+H]⁺.

Example 18:morpholino(4-(3-((2-phenoxypyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) methanoneand 4-iodo-2-phenoxypyridine in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent EtOAc/CH₃OH 94:6) to affordmorpholino(4-(3-((2-phenoxypyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(12.0 mg, 20%, AUC HPLC 98%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.39 (d, J=9.5 Hz, 1H), 8.32 (s, 1H), 8.27-8.23 (m,3H), 8.05 (d, J=9.5 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.45 (t, J=7.9 Hz,2H), 7.34 (d, J=5.0 Hz, 1H), 7.16 (m, 4H), 3.68-3.59 (m, 8H). ¹³C NMR(150 MHz, DMSO-d₆) δ (ppm): 168.4, 163.4, 153.5, 151.5, 148.2, 140.0,139.5, 137.4, 135.4, 133.1, 129.8, 127.9, 127.2, 126.6, 124.8, 121.3,120.2, 118.4, 112.3, 111.3, 95.8, 81.3, 72.5, 66.1 and 63.1; MS (ESI)m/z 502 [C₃₀H₂₃N₅O₃+H]⁺.

Example 19:(4-(3-((2-methoxypyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-iodo-2-methoxypyridine in a similar method to that described forExample 1. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((2-methoxypyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(99 mg, 75%, AUC HPLC 97%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.39 (d, J=9.5 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J=5.3 Hz, 1H),8.24 (d, J=8.3 Hz, 2H), 8.04 (d, J=9.5 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H),7.19 (dd, J=5.3, 1.2 Hz, 1H), 7.04 (s, 1H), 3.90 (s, 3H), 3.64 (bs, 6H),3.40 (bs, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 168.34, 163.76,151.46, 147.58, 139.76, 137.32, 135.42, 132.12, 127.79, 127.13, 126.52,118.25, 118.18, 111.55, 95.93, 80.46, 65.99, 53.34; MS (ESI) m/z 440[C₂₅H₂₁N₅O₃+H]⁺.

Example 20:(4-(3-((1H-pyrrolo[3,2-b]pyridin-6-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 6-iodo-1H-pyrrolo[3,2-b]pyridine in a similar method to thatdescribed for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((1H-pyrrolo[3,2-b]pyridin-6-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(2.4 mg, AUC HPLC 99%) as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ (ppm):8.47 (s, 1H), 8.27-8.25 (m, 3H), 8.16 (d, J=9.5 Hz, 1H), 8.07 (s, 1H),7.92 (d, J=9.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.47 (d, J=3.5 Hz, 1H),6.56 (d, J=3.5 Hz, 1H), 3.77-3.66 (m, 6H), 3.50-3.48 (bs, 2H); MS (ESI)m/z 449 [C₂₆H₂₀N₆O₂+H]⁺.

Example 21:(4-(3-((5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-fluoro-6-iodo-1H-pyrrolo[2,3-b]pyridine in a similar method tothat described for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(13 mg, AUC HPLC 98%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):10.06 (bs, 1H), 8.17 (s, 1H), 8.14 (d, J=8.3 Hz, 2H), 8.11 (d, J=9.5 Hz,1H), 7.71 (d, J=9.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 7.55 (d, J=8.3 Hz,2H), 7.52-7.51 (m, 1H), 6.45-6.44 (m, 1H), 3.90-3.48 (bs, 8H); ¹³C NMR(100 MHz, CDCl₃) δ (ppm): 169.66, 156.28, 151.65, 144.91, 139.75,139.25, 137.01, 136.60, 129.12, 127.91, 127.50, 127.50, 126.18, 124.45,121.29, 116.94, 114.56, 113.26, 101.51, 93.81, 80.59, 66.88, 46.20; MS(ESI) m/z 467 [C₂₆H₁₉FN₆O₂+H]⁺.

Example 22:((4-(3-((4-methylpyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-iodo-4-methylpyridine in a similar method to that described forExample 1. The reaction crude product was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford((4-(3-((4-methylpyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(6.2 mg, AUC HPLC 99.9%) as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ(ppm): 8.63 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.20 (d, J=8.4 Hz, 2H),8.14 (d, J=9.6 Hz, 1H), 8.07 (s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.62 (d,J=8.4 Hz, 2H), 7.38 (d, J=5.1 Hz, 1H), 3.78-3.68 (m, 6H), 3.50 (bs, 2H),2.64 (s, 3H); ¹³C NMR (100 MHz, CD₃OD) δ (ppm): 171.69, 153.54, 151.92,151.27, 149.33, 140.73, 138.96, 138.44, 137.89, 129.02, 128.61, 126.86,126.14, 121.78, 119.47, 114.50, 95.20, 84.19, 67.79, 20.54; MS (ESI) m/z424 [C₂₅H₂₁N₅O₂+H]⁺.

Example 23:(4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-iodo-1H-pyrrolo[2,3-b]pyridine in a similar method to thatdescribed for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(6.2 mg, AUC HPLC 98%) as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ (ppm):8.53 (d, J=1.7 Hz, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.13 (d, J=9.5 Hz, 1H),8.05-8.03 (m, 2H), 7.88 (d, J=9.5 Hz, 1H), 7.71 (d, J=3.3 Hz, 1H), 7.61(d, J=8.4 Hz, 2H), 6.67-6.66 (m, 1H), 3.77-3.65 (m, 6H), 3.49 (bs, 2H);¹³C NMR (100 MHz, CD₃OD) δ (ppm): 171.7, 153.4, 146.8, 145.8, 140.3,138.7, 138.3, 138.1, 132.7, 129.7, 129.0, 128.6, 126.7, 122.8, 119.1,115.0, 112.8, 103.0, 98.32, 77.66, 67.7; MS (ESI) m/z 449[C₂₆H₂₀N₆O₂+H]⁺.

Example 24:(4-(3-((1H-pyrrolo[2,3-b]pyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-iodo-1H-pyrrolo[2,3-b]pyridine in a similar method to thatdescribed for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) andpreparative HPLC (C18, eluents ACN/H₂O/HCOOH 0.01%) to afford(4-(3-((1H-pyrrolo[2,3-b]pyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(27 mg, 20%, AUC HPLC 96%) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.46 (bs, 1H), 8.44 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (dd, J=7.9, 1.4Hz, 1H), 8.16 (d, J=8.4 Hz, 2H), 8.14-8.08 (m, 2H), 7.74 (d, J=1.9 Hz,1H), 7.62-7.57 (m, 3H), 7.25 (dd, J=7.9, 4.7 Hz, 1H), 3.98-3.35 (m, 8H);¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.66, 151.43, 147.77, 144.66,138.75, 138.51, 136.96, 128.73, 128.65, 127.88, 127.47, 126.08, 120.92,117.21, 116.33, 114.27, 97.22, 91.78, 77.20, 66.88; MS (ESI) m/z 449[C₂₆H₂₀N₆O₂+H]⁺.

Example 25:morpholino(4-(3-((5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-iodo-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine in a similarmethod to that described for Example 1. The residue was purified bycolumn chromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5˜90:10) toaffordmorpholino(4-(3-((5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(5.3 mg, AUC HPLC 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.70-8.68 (m, 1H), 8.40-8.39 (m, 1H), 8.35 (d, J=9.5 Hz, 1H),8.29 (s, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.22 (s, 1H), 7.98 (d, J=9.5 Hz,1H), 7.59 (d, J=8.4 Hz, 2H), 3.78-3.42 (m, 8H); MS (ESI) m/z 517[C₂₇H₁₉F₃N₆O₂+H]⁺.

Example 26:(4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 2-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine in a similar method tothat described for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (62mg, 45%, AUC HPLC 96%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.41 (dd, J=4.8, 1.5 Hz, 1H), 8.12-8.10 (m, 4H), 7.93 (dd, J=8.0,1.5 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.11 (dd,J=7.8, 4.7 Hz, 1H), 6.90 (s, 1H), 4.08 (s, 1H), 3.75-3.48 (m, 8H); ¹³CNMR (100 MHz, CDCl₃) δ (ppm): 169.56, 151.75, 148.09, 144.80, 139.25,139.13, 137.21, 136.68, 129.02, 127.99, 127.41, 126.27, 122.02, 119.87,116.99, 116.57, 113.25, 105.94, 90.35, 83.01, 66.91, 29.50; MS (ESI) m/z463 [C₂₇H₂₂N₆O₂+H]⁺.

Example 27:(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-iodo-1H-benzo[d]imidazole in a similar method to that describedfor Example 1. The residue was purified by column chromatography (silicagel, eluent CH₂Cl₂/MeOH 95:5˜90:10) to afford(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(90 mg, 67%, AUC HPLC 99%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 8.35 (s, 1H), 8.32 (d, J=9.5 Hz, 1H), 8.21 (d, J=8.4 Hz, 2H),8.20 (s, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.91 (s, 1H), 7.70 (d, J=8.2 Hz,1H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (dd, J=8.2, 1.2 Hz, 1H), 3.79-3.32 (m,8H); ¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 168.52, 151.31, 143.81, 138.66,138.31, 137.19, 135.74, 127.84, 127.13, 126.34, 125.42, 117.50, 114.82,112.69, 99.59, 74.78, 66.04, 47.66; MS (ESI) m/z 449 [C₂₆H₂₀N₆O₂+H]⁺.

Example 28:(4-(3-((1H-pyrazol-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-iodo-1H-pyrazole in a similar method as described for Example 1.The residue was purified by column chromatography (silica gel, eluentCH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((1H-pyrazol-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(13.7 mg, 11%, AUC HPLC 99%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ (ppm): 8.28 (d, J=8.3 Hz, 2H), 8.07 (d, J=9.5 Hz, 1H), 8.02 (s, 1H),7.88 (s, 2H), 7.59-7.54 (m, 3H), 3.79-3.49 (m, 8H); ¹³C NMR (100 MHz,DMSO-d₆) δ (ppm): 169.77, 151.55, 138.72, 138.63, 136.91, 136.89,127.90, 127.54, 126.09, 116.57, 113.99, 102.58, 90.29, 66.88, 48.32,42.81; MS (ESI) m/z 399 [C₂₂H₁₈N₆O₂+H]⁺.

Example 29:(4-(3-((6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine in a similar method tothat described for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10) to afford(4-(3-((6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(24 mg, 35%, AUC HPLC 99%) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.75 (s, 1H), 8.39 (d, J=9.5 Hz, 1H), 8.33 (s, 1H), 8.27 (d,J=8.2 Hz, 2H), 8.04 (d, J=9.5 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.56-7.55(m, 1H), 7.18 (s, 1H), 6.68-6.64 (m, 1H), 3.65-3.41 (m, 8H), 2.57 (s,3H); ¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 168.33, 151.47, 150.94, 148.22,139.20, 139.15, 137.35, 135.62, 127.74, 127.10, 126.47, 126.32, 120.69,117.96, 117.53, 116.24, 111.99, 98.71, 96.08, 81.56, 65.97, 23.76; MS(ESI) m/z 463 [C₂₇H₂₂N₆O₂+H]⁺.

Example 30:4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-iodo-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile in a similar methodto that described for Example 1. The residue was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 0.95:5˜90:10) to afford4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile(15 mg, 21%, AUC HPLC 98%) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.59 (s, 1H), 8.42 (d, J=9.5 Hz, 1H), 8.39 (s, 1H), 8.28 (d,J=8.4 Hz, 2H), 8.07 (d, J=9.5 Hz, 1H), 8.04 (d, J=3.4 Hz, 1H), 7.90 (s,1H), 7.67 (d, J=8.4 Hz, 2H), 6.90 (d, J=3.4 Hz, 1H), 3.65-3.41 (m, 8H);¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 168.33, 151.66, 147.83, 139.87,139.58, 137.41, 135.51, 132.58, 127.76, 127.15, 126.57, 124.03, 122.98,121.55, 120.63, 118.39, 118.32, 111.47, 99.98, 94.43, 84.33, 65.98; MS(ESI) m/z 474 [C₂₇H₁₉N₇O₂+H]⁺.

Example 31:morpholino(4-(3-((5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

Step 1: tert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylatewas synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand tert-butyl4-iodo-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate in asimilar method to that described for Example 1. The residue was purifiedby column chromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5 to 90:10)to afford tert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(50 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.81(s, 1H), 8.20 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 8.12 (d, J=9.5 Hz, 1H),7.82 (d, J=4.0 Hz, 1H), 7.67 (d, J=9.5 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H),6.98 (d, J=4.0 Hz, 1H), 3.79-3.52 (m, 8H), 1.71 (s, 9H); MS (ESI) m/z617 [C₃₂H₂₇F₃N₆O₄+H]⁺.

Step 2: To a solution of tert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(50 mg, 0.081 mmol) in DCM (1 mL) was added TFA (1 mL) and the wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated and the reaction mixture was basified with NaHCO₃, dilutedwith EtOAc and washed with water and brine solution. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the reaction crude product which was purified by columnchromatography (silica gel, eluent CH₂Cl₂/MeOH 95:5˜90:10) to affordmorpholino(4-(3-((5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(36 mg, 86%, AUC HPLC 98%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 12.46 (s, 1H), 8.65 (s, 1H), 8.44-8.42 (m, 2H), 8.31 (d, J=8.4Hz, 2H), 8.11 (d, J=9.6 Hz, 1H), 7.89 (d, J=3.4 Hz, 1H), 7.67 (d, J=8.4Hz, 2H), 6.96 (d, J=3.4 Hz, 1H), 3.66-3.42 (m, 8H); ¹³C NMR (100 MHz,DMSO-d₆) δ (ppm): 168.3, 151.6, 149.6, 140.1, 139.7, 139.5, 137.4,135.4, 130.27, 127.6, 127.0, 126.6, 120.3, 119.0, 118.4, 116.0, 111.4,100.1, 92.3, 87.9, 65.9; MS (ESI) m/z 517 [C₂₇H₁₉F₃N₆O₂+H]⁺.

Example 32:morpholino(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(100 mg, 0.301 mmol), 4-bromopyridine hydrochloride (87.6 mg, 0.451mmol), PdCl₂(PPh₃)₂ (13.7 mg, 0.0195 mmol), CuI (5.7 mg, 0.030 mmol) andPPh₃ (27.6 mg, 0.105 mmol), in DMF (1.0 mL) was added DIPEA (1.0 mL) andpurged with N₂ for 10 min. The reaction mixture was heated at 70° C. ina sealed tube for 12 h and was concentrated in vacuo to dryness. Theresidue was purified by flash column chromatography (silica gel, eluentCH₂Cl₂/CH₃OH 94:6) to affordmorpholino(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(72.0 mg, 58.5%, AUC HPLC 97%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.69 (d, J=6.0 Hz, 2H), 8.38 (d, J=9.5 Hz, 1H), 8.31(s, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.04 (d, J=9.6 Hz, 1H), 7.66-7.60 (m,4H), 3.69-3.58 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.5,152.6, 150.1, 149.8, 139.4, 137.8, 135.5, 139.6, 127.9, 127.3, 126.6,124.9, 118.4, 111.5, 96.1, 81.1, 66.1, 47.6; MS (ESI) m/z 410[C₂₄H₁₉N₅O₂+H]⁺.

Example 33:(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) methanoneand 4-bromo-1H-pyrrolo[2,3-b]pyridine in a similar method to thatdescribed for Example 32. The reaction crude product was purified byflash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 96:4) toafford(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(18.0 mg, 25%, AUC HPLC 97%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 11.98 (s, 1H), 8.37 (d, J=9.5 Hz, 1H), 8.33 (s, 1H),8.30-8.24 (m, 3H), 8.04 (d, J=9.5 Hz, 1H), 7.69-7.64 (m, 3H), 7.29 (d,J=4.9 Hz, 1H), 6.74 (s, 1H), 3.69-3.56 (m, 8H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.6, 151.7, 148.4, 142.6, 139.4, 139.3, 137.5,135.8, 128.0, 127.7, 127.3, 126.6, 120.6, 120.0, 118.3, 116.7, 112.1,99.1, 96.1, 82.3, 66.1, and 48.7; MS (ESI) m/z 449 [C₂₆H₂₀N₆O₂+H]⁺.

Example 34:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-bromopyridin-2-amine in a similar method to that described forExample 32. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(14.0 mg, 18%, AUC HPLC 97%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.34 (d, J=9.5 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J=8.1Hz, 2H), 7.99 (d, J=9.6 Hz, 2H), 7.66-7.37 (m, 4H), 6.69-6.63 (m, 1H),6.18 (s, 1H), 3.68-3.64 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm):168.6, 159.9, 151.6, 148.6, 139.4, 137.4, 135.7, 130.2, 128.0, 127.3,126.6, 118.2, 113.0, 111.9, 109.2, 97.1, 78.8, 66.2, 48.0 and 42.2; MS(ESI) m/z 425 [C₂₄H₂₀N₆O₂+H]⁺.

Example 35:(4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)Methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine in a similar method tothat described for Example 32. The reaction crude product was purifiedby flash column chromatography (silica gel, eluent EtOAc/CH₃OH 90:10) toafford(4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (24.0 mg, 29%, AUC HPLC 98%) as a yellow solid; ¹H NMR (600MHz, DMSO-d₆) δ (ppm): 8.41 (s, 1H), 8.34 (d, J=4.6 Hz, 1H), 8.27 (d,J=7.8 Hz, 2H), 8.06 (d, J=7.7 Hz, 1H), 7.72 (d, J=2.7 Hz, 1H), 7.66 (d,J=7.9 Hz, 2H), 7.64-7.52 (m, 1H), 7.32 (d, J=4.6 Hz, 1H), 6.75 (d, J=2.7Hz, 1H), 3.88 (s, 3H), 3.63 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm):168.9, 152.1, 147.7, 142.8, 137.9, 136.1, 131.9, 129.2, 128.3, 127.6,121.3, 120.6, 118.6, 117.1, 98.4, 96.3, 66.5, 31.5; MS (ESI) m/z 463[C₂₇H₂₂N₆O₂+H]⁺.

Example 36:(4-(3-((1H-indol-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-bromo-1H-indole in a similar method to that described for Example32. The reaction crude product was purified by flash columnchromatography (silica gel, eluent EtOAc/CH₃OH 90:10) to afford(4-(3-((1H-indol-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(25.9 mg, 29.0%, AUC HPLC 97%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 11.45 (s, 1H), 8.37 (s, 1H), 8.27 (d, J=8.1 Hz, 2H),8.05-7.99 (m, 1H), 7.93 (t, J=7.4 Hz, 1H), 7.77 (td, J=7.9, 3.7 Hz, 2H),7.72 (dd, J=12.9, 7.5 Hz, 2H), 7.65 (d, J=8.2 Hz, 1H), 7.55-7.52 (m,2H), 7.32 (d, J=7.2 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 6.77 (s, 1H), 3.61(m, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.4, 151.5, 137.3, 135.8,135.5, 135.1, 134.4, 134.3, 130.4, 130.4, 128.8, 127.8, 127.2, 126.8,122.3, 121.1, 117.8, 117.4, 113.1, 112.4, 100.4, 98.4, 66.0; MS (ESI)m/z 448 [C₂₇H₂₁N₅O₂+H]⁺.

Example 37:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(4-bromopyridin-2-yl)acetamide in a similar method to thatdescribed for Example 32. The reaction crude product was purified byflash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 90:10) toaffordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide(24.7 mg, 29.0%, AUC HPLC 100%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 10.69 (s, 1H), 8.39 (t, J=7.8 Hz, 2H), 8.32 (d, J=8.6Hz, 2H), 8.25 (d, J=8.2 Hz, 2H), 8.05 (d, J=9.5 Hz, 1H), 7.65 (d, J=8.2Hz, 2H), 7.29 (d, J=4.7 Hz, 1H), 3.76-3.49 (m, 8H), 2.14 (s, 3H); ¹³CNMR (150 MHz, DMSO-d₆) δ (ppm): 169.7, 168.4, 152.4, 151.4, 148.7,139.7, 137.3, 135.5, 131.2, 127.9, 127.2, 126.6, 120.0, 118.2, 114.1,111.5, 96.7, 80.7, 79.2, 66.1, 47.7, 24.0; MS (ESI) m/z 467[C₂₆H₂₂N₆O₃+H]⁺.

Example 38:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(4-bromopyridin-2-yl)benzamide in a similar method to thatdescribed for Example 32. The reaction crude product was purified byflash column chromatography (silica gel, eluent EtOAc/CH₃OH 90:10) toaffordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide(40.8 mg, 43.0%, AUC HPLC 99%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 11.02 (s, 1H), 8.50 (d, J=4.9 Hz, 1H), 8.48 (s, 1H),8.40 (d, J=9.5 Hz, 1H), 8.34 (s, 1H), 8.28 (d, J=7.8 Hz, 2H), 8.06 (d,J=7.5 Hz, 3H), 7.66 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.3 Hz, 1H), 7.54 (t,J=7.5 Hz, 2H), 7.38 (d, J=4.9 Hz, 1H), 3.59 (m, 8H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.5, 166.4, 152.6, 151.5, 148.8, 139.7, 139.5,137.4, 135.5, 133.9, 132.2, 131.3, 128.4, 128.1, 127.9, 127.2, 126.6,120.5, 118.32, 115.61, 111.5, 96.8, 80.9, 66.0; MS (ESI) m/z 529[C₃₁H₂₄N₆O₃+H]⁺.

Example 39:(4-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 3-bromoimidazo[1,2-b]pyridazine in a similar method to thatdescribed for Example 32. The reaction crude product was purified byflash column chromatography (silica gel, eluent EtOAc/CH₃OH 93:7) toafford(4-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(31.5 mg, 50.8%, AUC HPLC 99%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.74 (dd, J=4.4; 1.3 Hz, 1H), 8.41-8.26 (m, 4H), 8.23(d, J=8.3 Hz, 2H), 8.04 (d, J=9.5 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.42(dd, J=9.1, 4.4 Hz, 1H), 3.66-3.54 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ(ppm): 168.4, 151.4, 145.1, 139.3, 138.8, 137.3, 135.5, 127.8, 127.2,126.5, 126.2, 119.4, 118.0, 112.0, 85.6, 85.3, 66.0, 42.0; MS (ESI) m/z450 [C₂₅H₁₉N₇O₂+H]⁺.

Example 40:(4-(3-((6-hydroxypyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-bromopyridin-2-ol a procedure similar to that described forExample 32. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-(3-((6-hydroxypyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(23.0 mg, 65%, AUC HPLC 98%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.34 (d, J=9.5 Hz, 1H), 8.19 (d, J=8.1 Hz, 2H), 8.15(s, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.61 (d, J=8.3 Hz, 3H), 6.43 (d, J=9.4Hz, 1H), 3.61 (m, 6H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.9, 161.7,151.7, 142.9, 141.0, 139.1, 139.0, 137.7, 136.1, 128.3, 127.6, 126.9,120.7, 118.0, 112.9, 95.4, 76.4, 66.5, 40.5, 40.3, 40.2, 40.1, 39.9,39.8, 39.6, 39.5; MS (ESI) m/z 426 [C₂₄H₁₉N₅O₃+H]⁺.

Example 41:(4-(3-((1H-indol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-bromo-1H-indole in a similar method to that described for Example32. The reaction crude product was purified by preparative HPLC (C18,eluents ACN/H₂O/HCOOH 0.1%) to afford(4-(3-((1H-indol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(1.7 mg, AUC HPLC 96%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ(ppm): 8.33 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.07-8.04 (m, 2H), 7.98 (s,1H), 7.59 (d, J=8.4 Hz, 2H), 7.55 (d, J=9.5 Hz, 1H), 7.48 (dd, J=8.4,1.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.29-7.27 (m, 1H), 6.61-6.60 (m,1H), 3.77-3.48 (m, 8H); ¹³CNMR (400 MHz, CDCl₃) δ (ppm): 169.7, 151.3,138.6, 138.4, 137.0, 136.8, 135.8, 127.9, 127.4, 126.0, 125.7, 125.3,124.9, 116.1, 114.4, 113.7, 111.2, 103.1, 100.6, 77.2, 73.5, 66.9; MS(ESI) m/z 448 [C₂₇H₂₁N₅O₂+H]⁺.

Example 42:(4-(3-((6-methoxypyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 5-bromo-2-methoxypyridine in a similar method to that described forExample 32. The reaction crude product was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 98:2) to afford(4-(3-((6-methoxypyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(50 mg, LC-MS 99%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.47 (s, 1H), 8.10 (d, J=7.9 Hz, 4H), 7.78 (dd, J=6.6 Hz, 1H),7.59-7.57 (m, 3H), 6.79 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.80-3.50 (m,8H); MS (ESI) m/z 440.4 [C₂₅H₂₁N₅O₃+H]⁺.

Example 43:2-chloro-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamideand Example 44:2-(methylamino)-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide

Step 1: Preparation of2-chloro-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide:The title compound was synthesized from(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand N-(4-bromopyridin-2-yl)-2-chloroacetamide in a similar method tothat described for Example 32. The compound was purified by preparativeTLC (eluent acetone/CH₂Cl₂ 1:1) to afford2-chloro-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamideas a brown solid (2.1 mg, AUC HPLC 97.4%). ¹H NMR (600 MHz, DMSO-d₆) δ(ppm): 11.05 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.39 (d, J=9.5 Hz, 1H),8.33 (d, J=3.3 Hz, 2H), 8.28 (d, J=8.3 Hz, 2H), 8.07 (d, J=9.5 Hz, 1H),7.68 (d, J=8.2 Hz, 2H), 7.36 (dd, J=5.1, 1.1 Hz, 1H), 4.41 (s, 2H),3.79-3.48 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.5, 165.9,151.8, 151.4, 149.0, 139.5, 137.4, 135.4, 131.6, 128.0, 127.2, 126.6,120.5, 118.3, 114.4, 111.4, 96.7, 81.1, 66.1, 43.5, 40.0; MS (ESI) m/z501 [C₂₆H₂₁ClN₆O₃+H]⁺.

Step 2: Preparation of2-(methylamino)-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide:

To a solution of2-chloro-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide(12 mg, 0.024 mmol) and ethanol:DMF (1:0.5, 1.5 mL) was added a solutionof methylamine in ethanol (33% wt) and the reaction stirred for 12 h atroom temperature. The reaction mixture was concentrated in-vacuo todryness. The crude product was purified by preparative TLC (eluentCH₂Cl₂/CH₃OH 92:8%) to afford2-(methylamino)-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide (1.8 mg, 15%, AUC HPLC 95%) as a light yellowsolid. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 8.42 (d, J=5.1 Hz, 1H), 8.39(d, J=9.5 Hz, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 8.26 (d, J=8.2 Hz, 2H),8.06 (d, J=9.6 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.33 (d, J=5.0 Hz, 1H),3.63 (m, 8H), 2.54 (d, J=4.6 Hz, 2H), 2.35 (s, 3H); MS (ESI) m/z 496[C₂₇H₂₅N₇O₃+H]⁺.

Example 45:(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(piperazin-1-yl)Methanone

Step 1: tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylatewas synthesized from tert-butyl4-(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylateand 4-bromo-7-azaindole in a similar method to that described forExample 32. The compound was purified by flash column chromatography(silica gel, eluent CH₂Cl₂/CH₃OH 90:10) to afford tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylate(34.8 mg, 27%). ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 11.99 (s, 1H), 8.39(d, J=9.5 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J=4.9 Hz, 1H), 8.27 (d, J=8.4Hz, 2H), 8.05 (d, J=9.5 Hz, 1H), 7.69-7.66 (m, 2H), 7.65 (s, 1H), 7.29(d, J=4.9 Hz, 1H), 6.74 (dd, J=3.3, 1.9 Hz, 1H), 3.42 (m, 4H), 3.35 (m,4H), 1.41 (s, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.6, 153.8,151.6, 148.4, 142.5, 139.3, 137.6, 135.7, 127.8, 127.6, 127.2, 126.6,120.6, 119.9, 118.1, 116.6, 112.0, 99.5, 99.0, 96.0, 82.2, 79.3, 40.0,28.0; MS (ESI) m/z 548 [C₃₁H₂₉N₇O₃+H]⁺.

Step 2: To a solution of tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylate(12:4 mg, 0.0226 mmol) and DCM (2.5 mL) was added TFA (0.5 mL) and themixture was stirred at room temperature for 12 h. The reaction mixturewas purified by preparative TLC (eluent CH₂Cl₂/CH₃OH 80:20) to afford(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(piperazin-1-yl)methanone (4.5 mg, 44%, AUC HPLC 97%) as a yellow oil. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 12.00 (s, 1H), 8.39 (d, J=9.5 Hz, 1H), 8.33 (s, 1H),8.29 (d, J=4.9 Hz, 1H), 8.26 (d, J=8.3 Hz, 2H), 8.04 (d, J=9.6 Hz, 1H),7.69-7.66 (m, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.29 (d, J=4.9 Hz, 1H), 6.74(dd, J=3.2, 1.7 Hz, 1H), 3.65 (m, 4H), 2.83 (m, 4H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 168.4, 158.0, 157.8, 151.6, 148.4, 142.5, 139.3,137.7, 135.6, 127.8, 127.6, 127.2, 126.6, 120.6, 119.9, 118.3, 118.2,116.6, 116.3, 112.07, 99.08, 96.0, 82.2, 40.0; MS (ESI) m/z 448[C₂₆H₂₁N₇O+H]⁺.

Example 46:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylatewas synthesized from tert-butyl4-(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylateand 4-bromo-2-aminopyridine in a similar method to that described forExample 32. The compound was purified by flash column chromatography(eluent CH₂Cl₂/CH₃OH 90:10) to afford tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylate(52.5 mg, 43%); ¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.12-8.08 (m, 3H),8.08-8.04 (m, 2H), 7.58 (dd, J=8.8, 1.6 Hz, 3H), 6.83 (dd, J=5.3, 1.4Hz, 1H), 6.70 (s, 1H), 4.58 (s, 2H), 3.65-3.30 (m, 8H), 1.47 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ (ppm): 169.8, 158.5, 154.6, 151.7, 148.4,139.7, 137.3, 136.7, 132.2, 132.1, 132.1, 128.6, 128.5, 128.0, 127.6,126.3, 117.1, 115.8, 110.1, 97.1, 80.6, 79.3, 47.6, 42.2, 28.4; MS (ESI)m/z 524 [C₂₉H₂₉N₇O₃+H]⁺

Step 2:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(piperazin-1-yl)methanonewas synthesized from tert-butyl4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)piperazine-1-carboxylatein a similar method to that described in step 2 of Example 45 synthesis.The reaction mixture was purified by preparative TLC (eluentCH₂Cl₂/CH₃OH 80:20) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(piperazin-1-yl)methanone(9.5 mg, 22%, AUC HPLC 95.9%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.36 (d, J=9.4 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J=7.8Hz, 2H), 8.01 (d, J=9.5 Hz, 1H), 7.98 (d, J=4.8 Hz, 1H), 7.62 (d, J=7.8Hz, 2H), 6.66 (d, J=4.9 Hz, 1H), 6.64 (s, 1H), 6.18 (s, 2H), 3.64 (m,4H), 2.82 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.4, 159.9,158.0, 148.6, 139.2, 137.7, 135.5, 130.1, 127.8, 127.2, 126.6, 118.1,116.3, 112.8, 111.7, 109.0, 97.0, 78.7, 47.5, 45.0; MS (ESI) m/z 424[C₂₄H₂₁N₇O+H]⁺.

Example 47:(4-(3-((2-((2-methylpyridin-3-yl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(20 mg, 0.045 mmol), 2-methylpyridin-3-amine (9.7 mg, 0.090 mmol)) in amixture of 1,4 dioxane and DMF (9:1, 1 mL) was added BINAP (5.6 mg,0.0090 mmol)), t-BuONa (13 mg, 0.135 mmol)) and then Pd₂(dba)₃ (4.2 mg,0.0045 mmol)). The resulting mixture was microwave at 90° C. for 24 handwas filtered. The filtrate was purified by column chromatography (silicagel, eluent EtOAc/CH₃OH 90:10) to afford(4-(3-((2-((2-methylpyridin-3-yl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (5.3 mg, 23%, AUC HPLC 98.7%) as a light yellowsolid. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 8.53 (s, 1H), 8.38 (d, J=9.5Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.16 (t, J=4.9 Hz, 2H),8.07 (dd, J=8.1, 1.4 Hz, 1H), 8.03 (d, J=9.5 Hz, 1H), 7.64 (d, J=8.4 Hz,2H), 7.21 (dd, J=8.0, 4.7 Hz, 1H), 7.05 (s, 1H), 6.93 (dd, J=5.2, 1.3Hz, 1H), 3.63 (m, 8H), 2.46 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm):168.4, 156.5, 151.6, 150.9, 148.1, 143.3, 139.7, 137.3, 135.6, 134.8,130.5, 129.7, 127.9, 127.2, 126.6, 124.3, 121.3, 118.2, 115.3, 111.1,96.6, 91.8, 79.6, 66.1, 63.0, 21.3; MS (ESI) m/z 516 [C₃₀H₂₅N₇O₂+H]⁺.

Example 48:morpholino(4-(3-((2-(pyridin-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand pyridin-2-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordmorpholino(4-(3-((2-(pyridin-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(9 mg, 32.4%, AUC HPLC 99%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 9.80 (s, 1H), 8.35-8.28 (m, 3H), 8.25-8.20 (m, 3H),8.05 (s, 1H), 8.00 (d, J=12.0 Hz, 1H), 7.62-7.61 (m, 1H), 7.62-7.61 (m,3H), 7.08 (d, J=6.0 Hz, 1H), 6.92 (t, J=6.0 Hz, 1H); ¹³C NMR (150 MHz,DMSO-d₆) δ (ppm): 169.1, 154.9, 154.4, 152.1, 148.7, 147.8, 139.8,139.7, 138.2, 137.6, 136.0, 131.1, 128.3, 127.6, 126.9, 118.8, 117.3,116.8, 112.9, 112.5, 112.0, 97.3, 80.1, 66.4; MS (ESI) m/z 502[C₂₉H₂₃N₇O₂+H]⁺.

Example 49:morpholino(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand pyridin-3-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) to affordmorpholino(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6yl)phenyl)methanone (12 mg, 42.8%, AUC HPLC 97%) as a light yellowsolid. ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.49 (s, 1H), 8.78 (d, J=2.6Hz, 1H), 8.30 (d, J=9.5 Hz, 1H), 8.25-8.22 (m, 2H), 8.18 (dd, J=9.2, 2.7Hz, 3H), 8.10 (dd, J=4.8, 1.5 Hz, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.61 (d,J=8.0 Hz, 2H), 7.31 (dd, J=8.3, 4.7 Hz, 1H), 7.02 (s, 1H), 6.96 (dd,J=5.1, 1.4 Hz, 1H), 3.55-3.32 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ(ppm): 169.1, 156.0, 152.1, 148.5, 142.1, 140.4, 139.9, 139.7, 138.3,137.6, 136.0, 131.0, 128.3, 127.6, 126.9, 125.4, 124.1, 118.8, 116.2,112.4, 112.0, 96.9, 80.2, 66.5, 48.1; MS (ESI) m/z 502 [C₂₉H₂₃N₇O₂+H]⁺.

Example 50:morpholino(4-(3-((2-(pyridin-4-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand pyridin-4-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (Silica gel, eluent CH₂Cl₂/CH₃OH 94:6) to affordmorpholino(4-(3-((2-(pyridin-4-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(12 mg, 26%, AUC HPLC 99%) as a off white solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 9.81 (s, 1H), 8.34-8.28 (m, 4H), 8.25 (s, 1H), 8.19(d, J=6.0 Hz, 2H), 7.98 (d, J=6.0 Hz, 1H), 7.68 (d, J=6.0 Hz, 2H), 7.62(d, J=12.0 Hz, 2H), 7.10 (s, 1H), 7.07 (s, 1H), 3.69-3.61 (m, 4H); ¹³CNMR (150 MHz, DMSO-d₆) δ (ppm): 169.1, 155.5, 152.1, 150.1, 148.5,148.1, 140.0, 139.7, 137.6, 136.0, 131.3, 128.3, 127.6, 126.9, 118.9,117.4, 113.3, 112.5, 111.9, 96.7, 80.6, 66.4 and 48.4; MS (ESI) m/z 502[C₂₉H₂₃N₇O₂+H]⁺.

Example 51:morpholino(4-(3-((2-(phenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand aniline in a similar method to that described for Example 47. Thereaction crude product was purified by preparative TLC (eluentCH₂Cl₂/CH₃OH 95:5) to affordmorpholino(4-(3-((2-(phenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(8.9 mg, 18%, AUC HPLC 99.7%) as a yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 9.22 (s, 1H), 8.38 (d, J=9.5 Hz, 1H), 8.30 (s, 1H),8.23 (d, J=5.7 Hz, 2H), 8.21 (s, 1H), 8.03 (d, J=9.5 Hz, 1H), 7.70-7.66(m, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.29 (dd, J=8.4, 7.5 Hz, 2H), 7.02 (s,1H), 6.95-6.91 (m, 2H), 3.62 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ(ppm): 168.4, 156.1, 151.6, 148.1, 141.1, 139.6, 139.3, 137.4, 135.6,130.3, 128.7, 127.9, 127.2, 126.6, 121.0, 118.5, 118.2, 115.0, 111.6,96.6, 79.5, 66.1, 40.0; MS (ESI) m/z 501 [C₃₀H₂₄N₆O₂+H]⁺.

Example 52:morpholino(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand o-toluidine in a similar method to that described for Example 47.The reaction crude product was purified by flash column chromatography(silica gel, eluent EtOAc/CH₃OH 90:10) to affordmorpholino(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(6.3 mg, 14%, AUC HPLC 99.9%) as a yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.42-8.34 (m, 2H), 8.27 (s, 1H), 8.19 (d, J=8.2 Hz,2H), 8.13 (d, J=5.0 Hz, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.62 (d, J=8.1 Hz,2H), 7.56 (d, J=7.9 Hz, 1H), 7.24 (d, J=7.4 Hz, 1H), 7.18 (t, J=7.6 Hz,1H), 7.04 (t, J=7.4 Hz, 1H), 6.86 (d, J=7.3 Hz, 2H), 3.62 (m, 8H), 2.23(s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.4, 157.2, 151.5, 148.4,139.6, 139.3, 138.5, 137.3, 135.6, 131.4, 130.6, 130.4, 127.9, 127.2,126.6, 126.2, 123.9, 118.2, 114.5, 111.6, 109.9, 96.8, 79.3, 66.1, 40.0,18.1; MS (ESI) m/z 515 [C₃₁H₂₆N₆O₂+H]⁺.

Example 53:morpholino(4-(3-((2-(thiazol-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand thiazol-2-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 96:4) to affordmorpholino(4-(3-((2-(thiazol-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(8.9 mg, 20%, AUC HPLC 98%) as a off white solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.35 (d, J=5.2 Hz, 1H), 8.31 (d, J=9.5 Hz, 1H), 8.27(s, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.99 (d, J=9.5 Hz, 1H), 7.62 (d, J=7.9Hz, 2H), 7.38 (d, J=3.6 Hz, 1H), 7.26 (s, 1H), 7.08 (d, J=5.2 Hz, 1H),7.03 (d, J=3.6 Hz, 1H), 3.58-3.51 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ(ppm): 169.1, 160.0, 152.5, 152.1, 147.8, 140.0, 139.8, 137.9, 137.6,136.0, 131.3, 128.3, 127.7, 126.9, 118.9, 117.2, 112.0, 111.9, 96.8,80.7, 72.7, 63.3 and 42.4; MS (ESI) m/z 508 [C₂₇H₂₁N₇O₂S+H]⁺.

Example 54:morpholino(4-(3-((2-(pyrimidin-4-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand pyrimidin-4-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) to affordmorpholino(4-(3-((2-(pyrimidin-4-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(18 mg, 26%, AUC HPLC 98%) as a off white solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 10.35 (s, 1H), 8.71 (s, 1H), 8.43 (d, J=6.0 Hz, 1H),8.38 (d, J=6.0 Hz, 1H), 8.31 (d, J=12.0 Hz, 2H), 8.27 (s, 1H), 8.21-8.18(m, 2H), 8.01-7.99 (m, 1H), 7.98 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.61(d, J=6.0 Hz, 2H), 7.20 (d, J=12.0 Hz, 1H), 3.58-3.53 (m, 4H); ¹³C NMR(150 MHz, DMSO-d₆) δ (ppm): 169.1, 159.2, 158.1, 156.7, 153.7, 152.1,148.9, 140.0, 139.8, 137.6, 136.0, 131.5, 128.3, 127.6, 126.9, 119.1,118.9, 114.4, 111.9, 108.9, 97.0, 80.8, 66.4, and 42.5; MS (ESI) m/z 503[C₂₈H₂₂N₈O₂+H]⁺.

Example 55:morpholino(4-(3-((2-((2-(trifluoromethyl)phenyl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 2-(trifluoromethyl)aniline in a similar method to that described forExample 47. The reaction crude product was purified by preparative TLC(eluent EtOAc/CH₃OH 95:5) to affordmorpholino(4-(3-((2-((2-(trifluoromethyl)phenyl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(3.3 mg, 13%, AUC HPLC 96.9%) as a off yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.48 (s, 1H), 8.37 (d, J=9.5 Hz, 1H), 8.28 (s, 1H),8.20 (d, J=8.3 Hz, 2H), 8.11 (d, J=5.1 Hz, 1H), 8.02 (d, J=9.5 Hz, 1H),7.73 (d, J=7.9 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H),7.63 (d, J=8.3 Hz, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.93 (dd,J=5.1, 1.3 Hz, 1H), 3.62 (m, 8H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm):168.5, 157.2, 151.6, 148.3, 139.7, 139.3, 138.3, 137.4, 135.6, 133.0,130.7, 128.4, 127.9, 127.2, 126.6, 126.5, 126.5, 124.9, 124.8, 118.3,115.6, 111.6, 110.8, 96.6, 79.7, 66.1, 47.7; MS (ESI) m/z 569[C₃₁H₂₃F₃N₆O₂+H]⁺

Example 56:morpholino(4-(3-((2-(pyrimidin-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand pyrimidin-2-amine in a similar method to that described for Example47. The reaction crude product was purified by flash columnchromatography (silica gel, eluent CH₂Cl₂/CH₃OH 94:6) to affordmorpholino(4-(3-((2-(pyrimidin-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6yl)phenyl)methanone (21 mg, 32.3%, AUC HPLC 95%) as a light brown solid;¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 9.99 (s, 1H), 8.59-8.47 (m, 3H),8.37-8.31 (m, 3H), 8.20 (d, J=7.8 Hz, 2H), 8.01 (d, J=9.6 Hz, 1H), 7.61(d, J=7.8 Hz, 2H), 7.20 (s, 1H), 7.01 (s, 1H), 3.42-3.37 (m, 4H); ¹³CNMR (150 MHz, DMSO-d₆) δ (ppm): 169.0, 159.3, 158.6, 158.5, 153.6,152.1, 149.1, 139.9, 137.7, 136.0, 132.1, 131.3, 128.5, 128.3, 127.7,127.0, 118.8, 114.5, 113.7, 112.0, 97.4, 80.5, 66.5, 48.1; MS (ESI) m/z503 [C₂₈H₂₂N₈O₂+H]⁺.

Example 57:morpholino(4-(3-((2-(m-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand m-toluidine amine in a similar method to that described for Example47. The residue was purified by preparative HPLC (C18, eluentsCH₃CN/H₂O/HCOOH 0.01%) to affordmorpholino(4-(3-((2-(m-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(1.8 mg, AUC HPLC 99%) as a yellow solid. ¹H NMR (400 MHz, CH₃OD) δ(ppm): 8.25 (d, J=8.3 Hz, 2H), 8.18 (d, J=9.5 Hz, 1H), 8.14-8.10 (m,2H), 7.96 (d, J=9.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.34-7.28 (m, 2H),7.18 (t, J=7.7 Hz, 1H), 6.99 (s, 1H), 6.89-6.87 (m, 1H), 6.84 (d, J=7.4Hz, 1H), 3.90-3.51 (m, 8H), 2.33 (s, 3H); MS (ESI) m/z 515[C₃₁H₂₆N₆O₂+H]⁺.

Example 58:morpholino(4-(3-((2-(p-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand p-toluidine in a similar method to that described for Example 47.The reaction crude product was purified by preparative HPLC (C18, eluentCH₃CN/H₂O/HCOOH 0.1%) to affordmorpholino(4-(3-((2-(p-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(2.2 mg, AUC HPLC 98%) as a brown solid. ¹H NMR (400 MHz, CH₃OD) δ(ppm): 8.24 (d, J=8.3 Hz, 2H), 8.17 (d, J=9.5 Hz, 1H), 8.14-8.10 (m,2H), 7.94 (d, J=9.5 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz,2H), 7.13 (d, J=8.3 Hz, 2H), 6.96 (s, 1H), 6.85 (d, J=8.3 Hz, 1H),3.85-3.46 (m, 8H), 2.31 (s, 3H); ¹³C NMR (100 MHz, CH₃OD) δ (ppm):171.79, 158.34, 153.62, 148.99, 140.89, 139.64, 139.48, 138.47, 137.94,133.30, 133.11, 130.57, 129.05, 128.70, 126.94, 121.66, 119.64, 116.27,114.38, 112.22, 98.06, 79.84, 67.85, 20.94; MS (ESI) m/z 515[C₃₁H₂₆N₆O₂+H]⁺.

Example 59:(4-(3-((2-(2-isopropylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 2-isopropylaniline in a similar method to that described for Example47. The reaction crude product was purified by preparative HPLC (C18,eluent CH₃CN/H₂O/HCOOH 0.1%) to afford(4-(3-((2-(2-isopropylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (5.63mg, 15%, AUC HPLC 96%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.18 (d, J=5.2 Hz, 1H), 8.09-8.04 (m, 4H), 7.60-7.55 (m, 3H),7.41-7.36 (m, 2H), 7.26-7.23 (m, 2H), 6.90-6.87 (m, 1H), 6.73 (s, 1H),6.61 (s, 1H), 4.78-3.30 (m, 8H), 3.24 (m, J=6.8 Hz, 1H), 1.25 (d, J=6.8Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.61, 157.88, 151.65,148.30, 143.88, 139.69, 139.24, 137.14, 136.58, 136.37, 132.27, 127.96,127.43, 126.74, 126.61, 126.28, 126.21, 125.72, 117.01, 115.96, 113.02,108.38, 97.21, 66.92, 28.03, 23.30; MS (ESI) m/z 543 [C₃₃H₃₀N₆O₂+H]⁺.

Example 60:(4-(3-((2-(biphenyl-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand biphenyl-2-amine in a similar method to that described for Example47. The reaction crude product was purified by preparative HPLC (C18,eluent CH₃CN/H₂O/HCOOH 0.1%) to afford(4-(3-((2-(biphenyl-2-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(6.4 mg, 17%, AUC HPLC 99%) as a brown solid. ¹H NMR (400 MHz, CH₃OD) δ(ppm): 8.18 (d, J=5.2 Hz, 1H), 8.11-8.07 (m, 4H), 7.82 (d, J=7.5 Hz,1H), 7.59 (t, J=8.7 Hz, 3H), 7.45-7.26 (m, 7H), 7.21-7.16 (m, 1H), 6.99(s, 1H), 6.91-6.89 (m, 1H), 6.60 (s, 1H), 4.16-3.08 (m, 8H); ¹³C NMR(100 MHz, CH₃OD) δ (ppm): 169.58, 156.12, 151.69, 148.37, 139.68,139.26, 138.65, 137.13, 136.90, 134.07, 132.10, 130.92, 129.26, 128.90,128.35, 127.97, 127.70, 127.43, 126.22, 123.70, 121.51, 117.08, 116.52,117.08, 116.52, 113.00, 109.92, 97.07, 79.65, 66.89; MS (ESI) m/z 577[C₃₆H₂₈N₆O₂+H]⁺.

Example 61: 3-methyl-N-(4-((6-(4-(morpholine-4carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide

To a solution of(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(30 mg, 0.07 mmol) in DCM (5 mL) was added 3-methylbenzoyl chloride (60mg, 0.35 mmol), DMAP (43 mg, 0.35 mmol) and TEA (22 mg, 0.21 mmol). Theresulting mixture was stirred at room temperature 6 h. The reactionmixture was then filtered and the filtrate was purified by preparativeHPLC (C18, eluent CH₃CN/H₂O/HCOOH 0.1%) to afford the mono and bisbenzamide derivatives3-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamideand3-methyl-N-(3-methylbenzoyl)-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide.3-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide(13.4 mg, 35%, AUC HPLC 99%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.82 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.18-8.11 (m, 4H), 7.88 (s,2H), 7.67-7.64 (m, 3H), 7.44-7.42 (m, 2H), 7.31 (d, J=5.6 Hz, 1H),4.11-3.34 (m, 8H), 2.48 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm):169.68, 165.95, 164.34, 151.81, 147.91, 139.86, 138.88, 137.11, 136.52,134.08, 133.21, 133.16, 128.82, 128.07, 127.92, 127.51, 126.21, 124.316,121.35, 117.19, 115.72, 112.94, 97.00, 80.98, 66.89, 53.42, 48.23,42.60, 21.41; MS (ESI) m/z 543 [C₃₂H₂₆N₆O₃+H]⁺.

3-methyl-N-(3-methylbenzoyl)-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide(6.2 mg, 14%, AUC HPLC 99%) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.40 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 4H), 7.70-7.52 (m,8H), 7.34-7.21 (m, 5H), 4.04-3.31 (m, 8H), 2.33 (s, 6H); ¹³C NMR (100MHz, CDCl₃) δ (ppm): 173.15, 169.55, 154.17, 151.40, 149.28, 140.10,138.61, 137.23, 136.47, 134.61, 133.04, 130.02, 128.44, 128.02, 127.50,126.34, 126.31, 123.58, 123.21, 117.41, 96.04, 81.83, 66.88, 21.29; MS(ESI) m/z 661 [C₄₀H₃₂N₆O₄+H]⁺.

Example 62:4-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide

The title compound was synthesized from(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-methylbenzoyl chloride in a similar method to that described forExample 61. The reaction crude product was purified by preparative HPLC(C18, eluent CH₃CN/H₂O/HCOOH 0.1%) to afford4-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide(4.48 mg, 12%, AUC HPLC 95%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.07 (s, 1H), 8.71 (s, 1H), 8.321-8.29 (m, 1H), 8.18-8.10 (m,4H), 7.89 (d, J=7.9 Hz, 2H), 7.64 (d, J=8.0 Hz, 3H), 7.34 (d, J=7.9 Hz,2H), 7.28-7.25 (m, 1H), 4.11-3.34 (m, 8H), 2.45 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ (ppm): 169.68, 165.66, 151.78, 151.68, 147.17, 143.31,140.05, 137.14, 136.51, 133.63, 131.05, 129.65, 129.53, 129.39, 128.08,127.53, 127.35, 126.23, 121.22, 117.26, 115.88, 97.00, 66.90, 21.58; MS(ESI) m/z 543 [C₃₂H₂₆N₆O₃+H]⁺.

Example 63:2-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide

The title compound was synthesized from(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 2-methylbenzoyl chloride in a similar method to that described forExample 61. The reaction crude product was purified by preparative HPLC(C18, eluent CH₃CN/H₂O/HCOOH 0.1%) to afford2-methyl-N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)benzamide(1 mg, AUC HPLC 99%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.73 (s, 1H), 8.29 (d, J=5.1 Hz, 1H), 8.18-8.10 (m, 4H), 7.71-7.61 (m,4H), 7.43 (t, J=7.4 Hz, 1H), 7.33-7.30 (m, 3H), 4.96-3.36 (m, 8H), 2.57(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.68, 165.89, 151.78,151.72, 147.69, 139.95, 138.92, 137.15, 136.54, 134.03, 133.36, 133.27,128.86, 128.09, 127.92, 127.52, 126.23, 124.31, 121.36, 117.21, 115.73,97.00, 81.19, 66.91, 21.41; MS (ESI) m/z 543 [C₃₂H₂₆N₆O₃+H]⁺.

Example 064:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)isonicotinamide

To a solution of isonicotinic acid (29 mg, 0.24 mmol) in DMF (5 mL) wereadded HATU (68 mg, 0.18 mmol), N-methyl morpholine (24 mg, 0.24 mmol)and(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(50 mg, 0.12 mmol). The reaction mixture was stirred at room temperatureunder inert atmosphere for 18 h, and was diluted with H₂O (10 mL) andextracted with DCM (3×10 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by flash column chromatography (C18, eluentsACN/H₂O/HCOOH 0.01%) to affordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)isonicotinamide(9.4 mg, 15%, AUC HPLC 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 11.40 (s, 1H), 8.85 (s, 2H), 8.53 (d, J=4.9 Hz, 1H), 8.46 (s,1H), 8.41 (d, J=9.4 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J=7.9 Hz, 2H), 8.08(d, J=9.6 Hz, 1H), 8.02 (d, J=4.8 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.44(d, J=4.6 Hz, 1H), 3.62-3.22 (m, 8H); ¹³C NMR (100 MHz, DMSO-d₆) δ(ppm): 168.36, 164.80, 152.03, 151.44, 149.46, 148.76, 139.65, 137.33,135.42, 131.44, 127.83, 127.11, 126.51, 122.11, 120.94, 115.61, 96.52,81.03, 69.22, 65.98; MS (ESI) m/z 530 [C₃₀H₂₃N₇O₃+H]⁺.

Example 65:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)nicotinamide

The title compound was synthesized from(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand nicotinic acid in a similar method to that described for Example 64.The crude residue was purified by column chromatography (C18, eluentsACN/H₂O/HCOOH 0.01%) to affordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)nicotinamide(19 mg, 27%, AUC HPLC 98%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 11.30 (s, 1H), 9.18 (s, 1H), 8.80 (d, J=4.2 Hz, 1H), 8.52 (d,J=5.0 Hz, 1H), 8.47 (s, 1H), 8.42-8.35 (m, 3H), 8.28 (d, J=8.3 Hz, 2H),8.07 (d, J=9.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.60 (dd, J=7.7, 5.0 Hz,1H), 7.42-7.41 (m, 1H), 3.83-3.52 (m, 8H); ¹³C NMR (100 MHz, DMSO-d₆) δ(ppm): 168.50, 165.11, 152.31, 151.50, 148.88, 148.82, 139.67, 139.49,137.36, 135.98, 135.48, 131.44, 129.82, 127.91, 127.18, 126.57, 123.51,120.76, 115.58, 111.44, 96.69, 80.99, 69.27, 66.04, 65.44, 62.60; MS(ESI) m/z 530 [C₃₀H₂₃N₇O₃+H]⁺.

Example 66:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)picolinamide

The title compound was synthesized from(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand picolinic acid in a similar method to that described for Example 64.The reaction crude product was purified by column chromatography (C18,eluents ACN/H₂O/HCOOH 0.01%) to affordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)picolinamide(39 mg, 61%, AUC HPLC 99%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 11.40 (s, 1H), 8.85 (s, 2H), 8.53 (d, J=4.9 Hz, 1H), 8.46 (s,1H), 8.41 (d, J=9.4 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J=7.9 Hz, 2H), 8.08(d, J=9.6 Hz, 1H), 8.02 (d, J=4.8 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.44(d, J=4.6 Hz, 1H), 3.62-3.22 (m, 8H); ¹³C NMR (100 MHz, DMSO-d₆) δ(ppm): 169.71, 162.71, 151.72, 151.41, 149.18, 148.36, 148.34, 139.83,139.37, 137.66, 137.09, 136.56, 132.88, 128.04, 127.53, 126.91, 126.19,122.53, 121.38, 117.16, 115.45, 113.00, 97.03, 80.70, 66.91, 48.35,42.74; MS (ESI) m/z 530 [C₃₀H₂₃N₇O₃+H]⁺.

Example 67:4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile

Step 1: Preparation of 4-methyl-3-((trimethylsilyl)ethynyl)benzonitrile:To a mixture of 3-bromo-4-methylbenzonitrile (0.5 g, 2.57 mmol),PdCl₂(PPh₃)₂ (117 mg, 0.167 mmol), PPh₃ (236 mg, 0.902 mmol) and CuI (50mg, 0.257 mmol) was added THF (15 mL) followed by TMS-acetylene (0.878mL, 6.18 mmol) and Et₃N (15 mL). The resulting mixture was stirred at90° C. for 12 h and was concentrated in vacuo. The residue was purifiedby flash column chromatography (silica gel, eluent hexanes/EtOAc 4:1) toafford 4-methyl-3-((trimethylsilyl)ethynyl)benzonitrile (0.398 g, 72%).¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.67 (d, J=1.7 Hz, 1H), 7.44 (dd,J=7.9, 1.8 Hz, 1H), 7.27 (dt, J=8.0, 0.8 Hz, 1H), 2.46 (s, 3H), 0.25 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 146.1, 135.6, 131.5, 130.3,124.7, 118.4, 109.9, 101.4, 101.4, 21.2, −0.0; MS (ESI) m/z 214[C₁₃H₁₅NSi+H]⁺.

Step 2: Preparation of 3-ethynyl-4-methylbenzonitrile: To a solution of4-methyl-3-((trimethylsilyl)ethynyl)benzonitrile (350 mg, 1.62 mmol) andTHF:MeOH (1:1, 8 mL), K₂CO₃ (247 mg, 1.79 mmol) was added and themixture stirred at room temperature for 30 min. The reaction mixture wasconcentrated in vacuo to dryness and then suspended between ethylacetate (10 mL) and saturated aqueous ammonium chloride (5 mL). Thelayers were separated and the aqueous layer extracted with ethyl acetate(2×10 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel, eluent hexanes/EtOAc 1:1) to afford3-ethynyl-4-methylbenzonitrile (0.118 g, 82%). ¹H NMR (600 MHz, CDCl₃) δ(ppm): 7.70 (d, J=1.7 Hz, 1H), 7.48 (dd, J=8.0, 1.8 Hz, 1H), 7.29 (dd,J=8.0, 0.9 Hz, 1H), 3.36 (s, 1H), 2.49 (s, 3H). ¹³C NMR (150 MHz, CDCl₃)δ (ppm): 146.3, 135.9, 131.9, 130.5, 123.7, 118.2, 110.1, 83.5, 80.2,21.1; MS (ESI) m/z 142 [C₁₀H₇N+H]⁺.

Step 3: Preparation of3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)-4-methylbenzonitrile:To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (90.5 mg,0.390 mmol), PdCl₂(PPh₃)₂ (12.4 mg, 0.017 mmol), PPh₃ (27.8 mg, 0.106mmol), CuI (6.73 mg, 0.035 mmol) in a mixture of THF and DMF (1:1, 2 mL)was added 3-ethynyl-4-methylbenzonitrile (50 mg, 0.354 mmol) and Et₃N (1mL). The resulting mixture was stirred at 90° C. for 4 h and wasconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, eluent hexanes/EtOAc 2:3) to afford3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)-4-methylbenzonitrile(71.6 mg, 69%). ¹H NMR (600 MHz, CDCl₃) δ (ppm): 8.07 (s, 1H), 7.98 (d,J=9.4 Hz, 1H), 7.88 (d, J=1.7 Hz, 1H), 7.57 (dd, J=7.9, 1.8 Hz, 1H),7.41 (dt, J=8.1, 0.6 Hz, 1H), 7.18 (d, J=9.4 Hz, 1H), 2.68 (s, 3H). ¹³CNMR (150 MHz, CDCl₃) δ (ppm): 148.3, 145.9, 138.9, 135.1, 132.0, 130.7,127.3, 123.9, 120.2, 118.3, 113.5, 110.2, 105.2, 96.3, 81.4, 21.3. MS(ESI) m/z 293 [C₁₆H₉ClN₄+H]⁺.

Step 4: Preparation of4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile:To a solution of3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)-4-methylbenzonitrile(35 mg, 0.119 mmol), (4-(4-methylpiperazine-1-carbonyl)phenyl)boronicacid (50 mg, 0.175 mmol) in a mixture of 1,4 dioxane and H₂O (1:1, 3 mL)was added sodium carbonate (63 mg, 0.595 mmol) andtetrakis-(triphenylphosphine) palladium (13.7 mg, 0.011 mmol). Theresulting mixture was heated in a microwave reactor at 110° C. for 4 h.Upon cooling to room temperature, the reaction mixture was extractedwith EtOAc (3×10 mL). The organic layers were combined, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) toafford4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile(41 mg, 75%, AUC HPLC 95%) as a yellow solid. ¹H NMR (DMSO-d₆) δ (ppm):8.38 (d, J=9.5 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.07 (d,J=1.7 Hz, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.81 (dd, J=7.9, 1.8 Hz, 1H),7.64-7.56 (m, 3H), 3.66-3.63 (m, 2H), 2.69 (s, 3H), 2.46-2.23 (m, 4H),2.21 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.3, 151.6, 145.4,139.2, 139.0, 137.9, 135.5, 134.2, 132.3, 131.0, 127.7, 127.2, 126.6,123.1, 118.6, 118.1, 111.9, 109.4, 95.5, 82.5, 45.6, and 20.8; MS (ESI)m/z 461 [C₂₈H₂₄N₆O+H]⁺.

Example 68:4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzamide

To a solution of4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile(30 mg, 0.065 mmol) in a mixture of DMSO, EtOH and H₂O (1:4:3, 4 mL)were added H₂O₂ (20 mL), followed by NaOH (6.0N, 20 mL). The resultingmixture was stirred at 40° C. for 3 hand was extracted with EtOAc (3×10mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH 95:5) toafford4-methyl-3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzamide(22 mg, 71%, AUC HPLC 96%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.36 (d, J=9.5 Hz, 1H), 8.26-8.19 (m, 3H), 8.11 (d,J=1.9 Hz, 1H), 8.05 (bs, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.86 (dd, J=7.9,1.9 Hz, 1H), 7.62-7.56 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.39 (bs, 1H),3.66-3.63 (m, 2H), 2.65 (s, 3H), 2.47-2.23 (m, 4H), 2.21 (s, 3H); ¹³CNMR (150 MHz, DMSO-d₆) δ (ppm): 168.2, 166.8, 151.5, 142.7, 139.0,138.4, 137.7, 135.5, 132.2, 130.0, 129.8, 128.1, 127.6, 127.0, 126.4,121.6, 117.7, 112.2, 97.0, 80.8, 54.6, 54.1, 45.5, 20.2; MS (ESI) m/z479 [C₂₈H₂₆N₆O₂+H]⁺.

Example 69:3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile

Step 1: Preparation of3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile: The titlecompound was synthesized from 3-bromo-6-chloroimidazo[1,2-b]pyridazineand 3-ethynylbenzonitrile in a similar method to that described in step3 of Example 67 synthesis. The reaction crude product was purified byflash column chromatography (silica gel, eluent Hexanes/EtOAc 70:30) toafford 3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile(234 mg, 71%); ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 8.36 (d, J=9.5 Hz,1H), 8.28 (s, 1H), 8.15 (t, J=1.6 Hz, 1H), 7.96 (ddt, J=8.0, 3.2, 1.4Hz, 2H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.5 Hz, 1H); ¹³C NMR (150MHz, DMSO-d₆) δ (ppm): 147.8, 139.5, 135.9, 134.6, 133.0, 130.3, 128.3,122.7, 121.1, 112.4, 117.9, 111.7, 99.5, 96.6, 77.8; MS (ESI) m/z 279[C₁₅H₇ClN₄+H]+.

Step 2: Preparation of3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile:The title compound was synthesized from3-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile and(4-(4-methylpiperazine-1-carbonyl)phenyl)boronic acid in a similarmethod to that described in step 4 of Example 67 synthesis. The reactioncrude product was purified by flash column chromatography (silica gel,eluent CH₂Cl₂/CH₃OH 95:5) to afford3-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)benzonitrile(16 mg, 40%, AUC HPLC 96%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.37 (d, J=9.5 Hz, 1H), 8.27 (s, 1H), 8.25-8.20 (m,2H), 8.16 (td, J=1.7, 0.7 Hz, 1H), 8.02 (d, J=9.5 Hz, 1H), 8.00-7.96 (m,1H), 7.94 (dt, J=7.9, 1.4 Hz, 1H), 7.70 (td, J=7.8, 0.6 Hz, 1H),7.62-7.57 (m, 2H), 3.66-3.64 (m, 2H), 2.41-2.27 (m, 4H), 2.20 (s, 3H);¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.3, 151.5, 139.4, 139.1, 137.7,135.8, 135.4, 134.4, 132.7, 130.3, 127.7, 127.2, 126.5, 123.1, 118.1,117.9, 112.3, 111.7, 96.3, 78.6, 54.5, 45.6, 40.0; MS (ESI) m/z 447[C₂₇H₂₂N₆O+H]⁺.

Example 70:morpholino(4-(3-((2-phenylpyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone

To a solution of(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(50 mg, 0.112 mmol), phenyl boronic acid (16.3 mg, 0.135 mmol) and 1,4Dioxane:H₂O (1:1, 2 mL) was added Pd(PPh₃)₄ (13.0 mg, 0.011 mmol) andNa₂CO₃ (35.8 mg, 0.336 mmol). The reaction mixture was stirred at 80° C.for 12 h. Solvents were evaporated and the crude material was purifiedby flash column chromatography (silica gel, eluent EtOAc/CH₃OH 95:5) toaffordmorpholino(4-(3-((2-phenylpyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(17 mg, 32%, AUC HPLC 97%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.74 (d, J=6.0 Hz, 1H), 8.29-8.27 (m, 2H), 8.23-8.20(m, 3H), 8.11-8.08 (m, 3H), 7.99 (dd, J=9.5, 2.8 Hz, 1H), 7.63-7.61 (m,2H), 7.56 (d, J=6.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.49-7.47 (m, 1H),3.41-3.37 (m, 2H); ¹³C NMR (600 MHz, DMSO-d₆) δ (ppm): 169.2, 157.0,152.2, 150.5, 138.1, 137.6, 135.9, 133.3, 131.2, 129.4, 128.3, 127.7,127.1, 126.9, 125.3, 124.7, 124.0, 121.7, 118.9, 96.9, 81.4, 66.4, 63.1,42.5; MS (ESI) m/z 486 [C₃₀H₂₃N₅O₂+H]⁺.

Example 71:(4-(3-((2-(methyl(phenyl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) Methanone

To a solution ofmorpholino(4-(3-((2-(phenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanone(8 mg, 0.0165 mmol) and dry DMF (1 mL) was added Potassium tert-butoxide(3.6 mg, 0.0320 mmol)) and the reaction mixture stirred at roomtemperature for 10 min, followed by addition of methyl iodide (1.8 L,0.288 mmol) and stirring at room temperature for 12 h. DMF was removedunder vacuum and the residue was purified by preparative TLC (eluentCH₂Cl₂/CH₃OH 95:5) to afford(4-(3-((2-(methyl(phenyl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino) methanone as a light yellow solid (3.7 mg, 45%, AUC. HPLC98.0%); ¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 8.33 (d, J=9.5 Hz, 1H), 8.24(d, J=5.1 Hz, 1H), 8.22 (s, 1H), 8.14 (d, J=8.3 Hz, 2H), 7.99 (d, J=9.5Hz, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.49 (t, J=7.9 Hz, 2H), 7.39-7.34 (m,2H), 7.30 (t, J=7.4 Hz, 1H), 6.85 (dd, J=5.1, 1.2 Hz, 1H), 6.57 (s, 1H),3.64 (m, 8H), 3.42 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.5,158.3, 151.4, 148.5, 145.8, 139.5, 139.3, 137.3, 135.5, 130.1, 130.0,127.9, 127.1, 126.5, 126.5, 126.0, 118.2, 113.9, 111.5, 109.0, 96.9,79.4, 66.1, 47.7, 38.2; MS (ESI) m/z 515 [C₃₁H₂₆N₆O₂+H]⁺.

Example 72:N-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)acetamide

To a solution of(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(20 mg, 0.0432 mmol) and DCM (2 mL) was added triethylamine (12.0 μL,0.0863 mmol) followed by acetyl chloride (6.1 μL, 0.0863 mmol). Themixture was stirred at room temperature for 12 h, and then concentratedin vacuo. The reaction crude product was purified by preparative TLC(eluent CH₂Cl₂/CH₃OH 95:5) to affordN-(4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)acetamide(6.4 mg, 29%, AUC HPLC 97%) as a yellow solid. ¹H NMR (600 MHz, DMSO-d₆)δ (ppm): 11.73 (s, 1H), 10.44 (s, 1H), 8.39 (d, J=9.5 Hz, 1H), 8.36 (s,1H), 8.28 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 8.05 (d, J=9.5 Hz, 1H),7.71-7.65 (m, 2H), 7.53 (dd, J=3.3; 2.5 Hz, 1H), 6.66 (dd, J=3.4, 1.9Hz, 1H), 3.63 (m, 8H), 2.13 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm):169.0, 168.4, 159.7, 151.5, 146.8, 146.4, 139.4, 137.4, 135.7, 127.9,127.1, 126.6, 126.1, 122.0, 118.1, 116.7, 111.9, 107.6, 99.1, 96.4,81.8, 66.0, 48.6, 24.0; MS (ESI) m/z 506 [C₂₈H₂₃N₇O₃+H]⁺.

Example 73:(4-(3-((6-(benzylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(20 mg, 0.0432 mmol) and DMF (1.5 mL) was added NaH (2 mg, 0.0475 mmol)and stirred for 15 minutes at room temperature. Benzyl bromide (6 μL,0.0475) in DMF (0.5 mL) was then added. The mixture was stirred at roomtemperature for 12 h, and then concentrated in vacuo. The reaction crudeproduct was purified by preparative TLC (eluent CH₂Cl₂/CH₃OH 95:5) toafford(4-(3-((6-(benzylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(1.8 mg, AUC HPLC 99%) as a light yellow solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.38 (d, J=9.5 Hz, 1H), 8.31 (s, 1H), 8.27-8.22 (m,2H), 8.02 (d, J=9.6 Hz, 1H), 7.67-7.62 (m, 2H), 7.33-7.29 (m, 2H), 7.25(d, J=7.4 Hz, 1H), 7.22 (d, J=3.4 Hz, 1H), 7.21-7.17 (m, 2H), 6.54 (s,1H), 6.52 (d, J=3.4 Hz, 1H), 5.98 (s, 2H), 5.33 (s, 2H), 3.61 (m, 8H);¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 168.8, 156.5, 152.0, 147.1, 139.7,139.1, 137.8, 136.2, 132.8, 128.9, 128.3, 127.6, 127.4, 127.0, 124.9,123.1, 118.5, 112.5, 111.8, 104.5, 100.0, 99.4, 96.6, 81.0, 66.5, 47.3,42.5; MS (ESI) m/z 554 [C₃₃H₂₇N₇O₂+H]⁺.

Example 74:4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide

Step 1: Preparation of 4-(imidazo[1,2-b]pyridazin-6-yl)benzamide: Amixture of 6-chloroimidazo[1,2-b]pyridazine (1.5 g, 9.76 mmol),4-carbamoylphenylboronic acid (1.93 g, 11.72 mmol), Na₂CO₃ (2.07 g,19.52 mmol) in 1,4-dioxane (30 mL) and water (8 mL) was stirred underArgon for 20 min. Pd(PPh₃)₄ (563 mg, 0.49 mmol) was added and thereaction mixture was heated at 100° C. for 16 h. The reaction mixturewas diluted with EtOAc and filtered through a short pad of celite. Thefiltrate was washed with EtOAc and dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica gel, eluent CHCl₃/MeOH 97:3) to afford4-(imidazo[1,2-b]pyridazin-6-yl)benzamide (1.6 g, 68.9%, LC-MS 90%) as abrown solid.

Step 2: Preparation of 4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzamide:To a solution of 4-(imidazo[1,2-b]pyridazin-6-yl)benzamide (1.6 g, 6.72mmol) in DMF (20 mL) was added NIS (1.82 g, 8.06 mmol) at roomtemperature and stirred at 90° C. for 4 h. The reaction mixture wassubjected to an aqueous work-up and dried to afford4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzamide (1.6 g, 65.5% as a greensolid.

Step 3: Preparation of4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide: Amixture of 4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzamide (1.6 g, 4.39mmol), ethynyltrimethylsilane (0.74 mL, 5.27 mmol), CuI (125.6 mg, 0.66mmol), and diisopropylethylamine (1.13 mL, 6.58 mmol) in DMF (20 mL) wasstirred under argon for 20 min. Pd(PPh₃)₄ (253 mg, 0.22 mmol) was addedand the reaction mixture was heated at 90° C. for 3 h. Water (2×100 mL)was added to the reaction mixture and the precipitate was isolated byfiltration and purified by column chromatography (silica gel, eluentCHCl₃/MeOH 97:3) to afford4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide(800 mg, 54.8%, LC-MS 94.7%) as a light green solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.33 (d, J=9.7 Hz, 1H), 8.22-8.01 (m, 7H), 7.50 (bs,1H), 0.32 (s, 9H); MS (ESI) m/z 335 [C₁₈H₁₈N₄OSi+H]⁺.

Step 4: Preparation of4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzamide: To a solution of4-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide(500 mg, 1.5 mmol) in a mixture of THF, EtOH and H₂O (1:1:1, 15 mL) wasadded LiOH.H₂O (126 mg, 3 mmol) and the reaction mixture was stirred atroom temperature for 2 h. The solvents were evaporated under reducedpressure and the residue was diluted with EtOAc and washed in turn withwater and brine solution. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waswashed with diethyl ether and n-pentane to afford4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzamide (305 mg, 77.8%, LC-MS96.6%) as a green solid. ¹H NMR (400 MHz, DMSO d₆) δ (ppm): 8.33 (d,J=9.7 Hz, 1H), 8.20-7.90 (m, 7H), 7.52 (bs, 1H), 5.02 (s, 1H); MS (ESI)m/z 261 [C₁₅H₁₀N₄O+H]⁺.

Step 5: Preparation of tert-butyl4-((6-(4-carbamoylphenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamate:A mixture of 4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzamide (300 mg,1.14 mmol), tert-butyl 4-bromopyridin-2-ylcarbamate (374 mg, 1.37 mmol),CuI (32.37 mg, 0.17 mmol), and DIPEA (0.3 mL, 1.72 mmol) in DMF (10 mL)was stirred under argon for 20 min. Pd(PPh₃)₄ (69.3 mg, 0.06 mmol) wasadded and the reaction mixture was heated at 90° C. for 3 h. Water(2×100 mL) was added and the solid that has precipitated was isolated byfiltration to give the reaction crude product which was purified bycolumn chromatography (silica gel, eluent CHCl₃/MeOH 97:3) to affordtert-butyl4-((6-(4-carbamoylphenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamatemixed with its diboc analog (260 mg, mixture of mono and diboccompounds) as a light green solid.

Step 6: Preparation of4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide:To a solution of tert-butyl4-((6-(4-carbamoylphenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamate(260 mg, 0.57 mmol) in DCM (10 mL) was added TFA (2 mL) at 0° C. andstirred at room temperature for 3 h. The reaction mixture was dilutedwith water and basified with NaHCO₃, extracted with CHCl₃, and washedwith brine solution. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced. The crude product was purified by flashcolumn chromatography (silica gel, eluent CHCl₃/MeOH 96:4) to afford4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzamide(120 mg, 59.4%, LC-MS 95.3%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO d₆) δ (ppm): 8.37 (d, J=9.6 Hz, 1H), 8.26-8.22 (m, 3H), 8.12-8.04(m, 4H), 7.99 (d, J=5.2 Hz, 1H), 7.51 (bs, 1H), 6.66-6.63 (m, 2H), 6.17(s, 2H); MS (ESI) m/z 355.12 [C₂₀H₁₄N₆O+H]⁺.

Example 75:4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine

Step 1: Preparation of6-chloro-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine: to asolution of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (200 mg, 0.716mmol), and THF (2 mL) was added PdCl₂(PPh₃)₂ (25 mg, 0.035 mmol), CuI(13.6 mg, 0.071 mmol), Et₃N (1 mL) and TMS acetylene (102 μL, 0.716mmol) and then the reaction mixture was stirred at room temperature for12 h. The reaction mixture was concentrated in vacuo to dryness and thenpurified by flash column chromatography (silica gel, eluentHexanes/EtOAac 85:15) to afford6-chloro-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (153 mg,86%).

Step 2: Preparation of 6-chloro-3-ethynylimidazo[1,2-b]pyridazine: to asolution of 6-chloro-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine(170 mg, 0.682 mmol) in a mixture of THF and MeOH (1:1, 3 mL) was addedK₂CO₃ (113 mg, 0.819 mmol) and the mixture stirred at room temperaturefor 30 min. The reaction mixture was concentrated in vacuo to drynessand the residue was suspended in a mixture ethyl acetate (6 mL) andsaturated aqueous ammonium chloride (3 mL). The aqueous layer extractedwith ethyl acetate (2×8 mL) and the combined extracts were dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, eluent hexanes/EtOAc 85:15)to afford 6-chloro-3-ethynylimidazo[1,2-b]pyridazine (68 mg, 56.3%).

Step 3: Preparation of4-(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine: to asolution of 6-chloro-3-ethynylimidazo[1,2-b]pyridazine (130 mg, 0.734mmol) in a mixture of 1,4 dioxane and H₂O (2:1, 6 mL) was added(4-(morpholinomethyl)phenyl)boronic acid (238 mg, 0.881 mmol), sodiumcarbonate (389 mg, 3.67 mmol) and tetrakis-(triphenylphosphine)palladium(84.8 mg, 0.073 mmol). The resulting mixture was heated at 80° C. in amicrowave apparatus for 5 h. The reaction mixture was extracted withEtOAc (3×10 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (silica gel, eluent hexanes/EtOAc 20:80)to afford 4-(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine(87 mg, 37.3%); MS (ESI) m/z 319 [C₁₉H₁₈N₄O+H]⁺.

Step 4: Preparation of4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine:to a solution of4-(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine (20 mg,0.062 mmol) and DMF (1 mL) was added 4-bromo-1H-pyrrolo[2,3-b]pyridine(18.5 mg, 0.094 mmol), PdCl₂(PPh₃)₂ (2.8 mg, 0.004 mmol), CuI (1.2 mg,0.006 mmol), PPh₃ (5.76 mg, 0.022 mmol) and DIPEA (1 mL). The resultingmixture was stirred at 90° C. for 12 h. Upon cooling to roomtemperature, DMF was then removed in vacuo and the resulting residue waspurified by flash column chromatography (eluent CH₂Cl₂/CH₃OH 95:5) toafford4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzyl)morpholine(3.0 mg, 11.1%, AUC HPLC 94%) as a light yellow solid; ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 8.34 (s, 1H), 8.21 (d, J=9.6 Hz, 1H), 8.03 (d, J=7.9Hz, 3H), 7.83-7.76 (m, 3H), 7.50 (d, J=7.9 Hz, 3H), 3.59 (t, J=4.8 Hz,4H), 3.55 (s, 2H), 2.41-2.36 (m, 4H); MS (ESI) m/z 435 [C₂₆H₂₂N₆O+H]⁺.

Example 76:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone

To a solution of(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(160 mg, 0.46 mmol) in acetonitrile (6 mL) under inert atmosphere wasadded 4-iodopyridin-2-amine (132 mg, 0.60 mmol), Pd(PPh₃)₄ (26.6 mg,0.02 mmol), CuI (8.8 mg, 0.05 mmol) and 3 mL of DIPEA. The reactionmixture was heated at 70° C. for 2.5 h, was diluted with water (10 mL)and extracted with dichloromethane (25 mL×3). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography (silica gel, eluent DCM/Methanol 94:6) and washed withsaturated NaHCO₃ solution (5 mL×2). The organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure and high vacuumto afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone (91.2 mg, 45%, AUC HPLC 99.08%) asyellow solid mp: 120-122° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.20-8.00(m, 5H), 7.70-7.50 (m, 3H), 6.85 (d, J=4.8 Hz, 1H), 6.71 (s, 1H), 4.52(bs, 2H), 3.84 (bs, 2H) 3.49 (bs, 2H), 2.60-2.30 (m, 4H), 2.21 (s, 3H);¹³C NMR (400 MHz, CDCl₃) δ (ppm): 169.49, 158.41, 151.76, 148.31,139.52, 139.20, 137.61, 136.40, 132.03, 127.88, 127.38, 126.12, 117.08,115.73, 113.03, 110.05, 97.00, 79.26, 46.02; MS (ESI) m/z 438.20[C₂₅H₂₃N₇O+H]⁺.

Example 77:4-(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one

The title compound was synthesized in a similar fashion as described forExample 76 starting from4-(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one(130 mg, 0.28 mmol) and 4-ethynylpyridin-2-amine hydrochloride (56.29mg, 0.36 mmol). The reaction crude product was purified by flash columnchromatography (silica gel, eluent DCM/Methanol 94:6) and washed withNaHCO₃ (5 mL×3). The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford4-(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one(96 mg, 0.21 mmol, 76%, AUC HPLC 96.48%) as yellow solid mp:193.6-194.6° C. ¹H NMR (400 MHz, DMSO) δ (ppm): 8.38 (d, J=9.5 Hz, 1H),8.27 (s, 1H); 8.23 (d, J=8.0 Hz, 2H), 8.03 (d, J=9.5 Hz, 1H), 7.99 (d,J=5.1 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 6.75-6.55 (m, 2H), 6.17 (s, 2H),4.30-3.50 (m, 4H), 3.45-3.30 (m, 2H), 2.88 (s, 3H); ¹³C NMR (400 MHz,DMSO) δ (ppm): 168.74, 164.74, 159.96, 151.49, 148.61, 142.99, 139.46,139.24, 130.14, 128.03, 127.29, 126.58, 118.17, 112.91, 111.81, 109.05,97.11, 78.74, 33.71; MS (ESI) m/z 452.10[C₂₅H₂₁N₇O₂+H]⁺.

Example 78:(4-(3-((6-aminopyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

Step 1: Preparation of tert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamate:To a solution of(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (500mg, 1.15 mmol) and diisopropylethylamine (0.4 mL, 2.30 mmol) inacetonitrile (10 mL) were successively added Pd(PPh₃)₄ (66 mg, 0.057mmol), PPh₃ (15 mg, 0.057 mmol), CuI (32.8 mg, 0.172 mmol) andtert-butyl 5-ethynylpyridin-2-ylcarbamate (274 mg, 1.26 mmol). Thereaction mixture was heated at 80° C. for 10 h under argon and wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluent methanol/dichloromethane 3:97) toafford tert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamate(300 mg, 40%, LC-MS 86%) as a yellow solid. ¹H NMR (400 MHz, (DMSO-d₆) δ(ppm): 10.15 (s, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.35 (d, J=9.2 Hz, 1H),8.21-8.14 (m, 2H), 8.01-7.99 (m, 2H), 7.92 (d, J=8.8 Hz, 1H), 7.81-7.75(m, 1H), 7.64 (d, J=8.4 Hz, 2H), 3.65-3.41 (m, 8H), 1.49 (s, 9H); MS(ESI) m/z: 525.25 [C₂₉H₂₈N₆O₄+H]⁺.

Step 2: Preparation of(4-(3-((6-aminopyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone:A solution of tert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-ylcarbamate(300 mg, 0.49 mmol) and trifluoroacetic acid (3 mL) in dichloromethane(10 mL) was stirred at room temperature for 3 h and was concentratedunder reduced pressure. The residue was basified with an aqueoussolution of saturated NaHCO₃ solution, extracted with 5% methanol indichloromethane. The organic layer was washed with water and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC to afford(4-(3-((6-aminopyridin-3-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(120 mg, 71%, AUC HPLC 98%) as a yellow solid. ¹H NMR (400 MHz,(DMSO-d₆) δ (ppm): 8.33 (d, J=9.6 Hz, 1H), 8.21-8.18 (m, 3H), 8.13 (s,1H), 7.97 (d, J=9.2 Hz, 1H), 7.63-7.58 (m, 3H), 6.53-6.49 (m, 3H),3.66-3.62 (m, 8H); MS (ESI) m/z: 425.24 [C₂₄H₂₀N₆O₂+H]⁺.

Example 79:(4-(((3-amino-4-fluorophenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

To a solution of 2-fluoro-5-iodoaniline (342 mg, 1.44 mmol) anddiisopropylethylamine (0.43 mL, 2.4 mmol) in acetonitrile (10 mL) underargon were successively added Pd(PPh₃)₄ (69 mg, 0.0602 mmol), PPh₃ (15.7mg, 0.0602 mmol), CuI (34.3 mg, 0.18 mmol) and(4-(3-ethynylimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(400 mg, 1.20 mmol), the reaction mixture was heated at 80° C. for 4 h.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, eluentdichloromethane/methanol 3:97) and by preparative HPLC to afford(4-(3-((3-amino-4-fluorophenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(150 mg, 28.2%, AUC HPLC 99%) as a pale yellow solid. ¹H NMR (400 MHz,(DMSO-d₆) δ (ppm): 8.33 (d, J=9.2 Hz, 1H), 8.21 (d, J=8.4 Hz, 2H), 8.13(s, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.26 (dd,J=12.0, 2.0 Hz, 1H), 7.17 (dd, J=8.4, 2.0 Hz, 1H), 6.82-6.78 (m, 1H),5.76 (bs, 2H), 3.66-3.37 (m, 8H); MS (ESI) m/z: 442.26 [C₂₅H₂₀FN₅O₂+H]⁺.

Example 80:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-fluorophenyl)(morpholino)methanoneFormate Salt

The title compound was synthesized in a similar fashion as described forExample 76 starting from(2-fluoro-4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(100 mg, 0.221 mmol) and 4-ethynylpyridin-2-amine hydrochloride (41 mg,0.265 mmol). The solvents were then removed in vacuo and the resultingresidue was purified by flash column chromatography (silica gel, eluentCH₂Cl₂/CH₃OH 90:10) and by preparatory HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-fluorophenyl)(morpholino)methanoneformate salt (38.8 mg, 36%, AUC HPLC 99.8%) as a light green solid; ¹HNMR (600 MHz, DMSO-d₆) δ 8.40 (d, J=9.5 Hz, 1H), 8.30 (s, 1H), 8.13 (s,1H), 8.10-8.04 (m, 3H), 8.00 (d, J=5.3 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H),6.72-6.65 (m, 2H), 6.35 (s, 2H), 3.68 (m, 4H), 3.56 (t, J=4.7 Hz, 2H);¹³C NMR (150 MHz, DMSO-d₆) δ 163.4, 163.0, 159.4, 158.7, 157.1, 150.4,139.8, 137.8, 130.5, 129.8, 126.6, 125.3, 123.5, 118.1, 114.4, 112.8,111.7, 109.4, 96.9, 79.1, 66.0, 47.0, 41.9; MS (ESI) m/z 443[C₂₄H₁₉FN₆O₂+H]⁺

Example 81:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-methylphenyl)(morpholino)methanoneFormate Salt

The title compound was synthesized in a similar fashion as described forExample 76 starting from(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)-2-methylphenyl)(morpholino)methanone(100 mg, 0.223 mmol) and 4-ethynylpyridin-2-amine hydrochloride. Thereaction cude product was purified by flash column chromatography(eluent EtOAc/CH₃OH 85:15) and by preparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-methylphenyl)(morpholino)methanoneformate salt (62.9 mg, 58%, AUC HPLC 96.2%) as a light yellow solid; ¹HNMR (600 MHz, DMSO-d₆) δ 8.37 (d, J=9.6 Hz, 1H), 8.28 (s, 1H), 8.13 (s,1H), 8.05 (d, J=1.7 Hz, 1H), 8.03-7.98 (m, 3H), 7.42 (d, J=7.9 Hz, 1H),6.74-6.69 (m, 2H), 6.53 (s, 1H), 3.68 (m, 4H), 3.52 (m, 2H), 3.19 (m,2H), 2.36 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 168.0, 163.0, 158.7,151.7, 146.3, 139.6, 137.9, 134.9, 131.2, 128.9, 126.7, 126.5, 124.6,118.3, 112.8, 111.5, 109.8, 96.7, 66.2, 46.7, 41.4, 18.8; MS (ESI) m/z439 [C₂₅H₂₂N₆O₂+H]⁺

Example 82:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-chlorophenyl)(morpholino)methanone

The title compound was synthesized in a similar fashion as described forExample 76 starting from(2-chloro-4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanoneand 4-ethynylpyridin-2-amine (98.97 mg, 0.64 mmol). The reaction crudeproduct was purified by flash column chromatography (silica gel,DCM/Methanol 94:6) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-chlorophenyl)(morpholino)methanone(53.69 mg, 0.12 mmol, 27.4%, AUC HPLC 99.36%) as yellow solid, mp:193.7-194.8° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.25-8.05 (m, 4H), 8.00(d, J=8.0 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.87(s, 1H), 6.76 (s, 1H), 4.70 (bs, 2H), 4.00-3.88 (m, 1H), 3.87-3.78 (m,3H), 3.77-3.58 (m, 2H), 3.45-3.20 (m, 2H); ¹³C NMR (400 MHz, CDCl₃)166.26, 158.08, 150.50, 147.50, 139.94, 138.94, 137.52, 137.00, 132.38,131.42, 128.67, 128.41, 126.45, 126.03, 116.73, 115.65, 113.09, 110.32,97.17, 80.00, 66.80, 66.72, 47.19, 42.17; MS (ESI) m/z 459.10[C₂₄H₁₉ClN₆O₂+H]⁺.

Example 83:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-(trifluoromethyl)phenyl)(morpholino)methanone

The title compound was synthesized in a similar fashion as described forExample 76 starting from(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)-2-(trifluoromethyl)phenyl)(morpholino)methanone (130 mg, 0.26 mmol) and 4-ethynylpyridin-2-amine(60 mg, 0.39 mmol), Pd(PPh₃)₄ (14.96 mg, 0.013 mmol). The reaction crudeproduct was purified by flash column chromatography (silica gel, eluentDCM/methanol 96:4) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-2-(trifluoromethyl)phenyl)(morpholino)methanone(41.99 mg, 0.085 mmol, 32.9%, AUC HPLC 97.91%) as yellow solid mp:258.5-258.9° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.28 (d,J=7.2 Hz, 1H), 8.20-8.15 (m, 3H), 7.63 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 6.85 (d, J=4.8 Hz, 1H), 6.72 (s, 1H), 4.71 (s, 2H), 4.00-3.87(m, 1H), 3.86-3.74 (m, 3H), 3.67-3.56 (m, 2H); 3.30-3.20 (m, 2H); ¹³CNMR (400 MHz, CDCl₃) δ (ppm): 166.69, 154.42, 144.96, 144.05, 137.87,136.53, 136.35, 132.67, 130.94, 128.42, 127.93, 126.32, 125.66, 125.61,119.16, 109.62, 109.55, 105.63, 66.61, 66.27, 47.53, 42.22; MS (ESI) m/z493.10 [C₂₅H₁₉F₃N₆O₂+H]⁺.

Example 84:N-(4-((6-(4-(4-methyl-3-oxopiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide

The title compound was synthesized in a similar fashion as described forExample 76 starting from4-(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one(110 mg, 0.24 mmol) and N-(4-ethynylpyridin-2-yl)acetamide (49.50 mg,0.31 mmol). The reaction crude product was purified by flash columnchromatography (silica gel, eluent DCM/Methanol 95:5) to giveN-(4-((6-(4-(4-methyl-3-oxopiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide(56.64 mg, 0.11 mmol, 48%, AUC HPLC 98.85%) as yellow solid mp:258.2-259.5° C. ¹H NMR (400 MHz, DMSO) δ (ppm): 10.69 (s, 1H), 8.42-8.37(m, 2H), 8.40-8.30 (m, 2H), 8.27 (d, J=8.3 Hz, 2H), 8.07 (d, J=9.5 Hz,1H), 7.70 (d, J=8.3 Hz, 2H), 7.30 (dd, J=5.0, 1.3 Hz, 1H), 4.30-3.50 (m,4H), 3.40 (bs, 2H), 2.88 (s, 3H), 2.14 (s, 3H); ¹³C NMR (400 MHz, DMSO)δ (ppm): 170.25, 168.69, 152.88, 151.89, 149.16, 140.19, 137.26, 136.32,131.73, 128.49, 127.66, 127.03, 120.50, 118.73, 114.63, 111.97, 97.20,81.11, 55.33, 34.11, 24.45; MS (ESI) m/z 494.20 [C₂₇H₂₃N₇O₃+H]⁺.

Example 85:4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one

The title compound was synthesized in a similar fashion as described forExample 76 starting from4-(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one(101 mg, 0.22 mmol) and 4-ethynyl-1H-pyrrolo[2,3-b]pyridine (40.5 mg,0.29 mmol). The reaction crude product was purified by flash columnchromatography (silica gel, eluent DCM/Methanol 92:8) to give4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one(72.6 mg, 0.15 mmol, 69%, AUC HPLC 99.85%) as yellow solid mp:207.2-208.2° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.03 (s, 1H), 8.34 (d,J=5.0 Hz, 1H), 8.20-8.15 (m, 3H), 8.12 (d, J=9.4 Hz, 1H), 7.68-7.60 (m,3H), 7.45-7.40 (m, 1H), 7.31 (d, J=5.0 Hz, 1H), 6.86 (s, 1H), 4.45-3.60(m, 4H), 3.46 (bs, 2H), 3.04 (s, 3H); ¹³C NMR (400 MHz, DMSO) δ (ppm):168.74, 164.74, 152.02, 148.84, 142.99, 139.80, 139.74, 137.32, 136.52,128.39, 128.07, 127.70, 127.02, 121.04, 120.41, 118.62, 117.10, 112.52,99.51, 96.48, 82.66, 34.11; MS (ESI) m/z 476.10 [C₂₇H₂₁N₇O₂+H]⁺.

Example 86:4-(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)benzoyl)-1-methylpiperazin-2-one

A mixture of(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(500 mg 1.118 mmol in DMF (10 mL), 5-ethynyl-1H-benzo[d]imidazole (190mg, 1.342 mmol), CuI (32 mg, 0.167 mmol), DIPEA (0.422 mL, 2.36 mmol)and Pd(PPh₃)₄ (64 mg, 0.0520 mmol) in DMF was heated at 80° C. for 4 hunder argon. The reaction mixture was diluted with water (25 mL),extracted with ethyl acetate (50 mL), and washed with brine solution.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 90:10) to give(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(160 mg, 29%, HPLC 95%) as a yellow solid. ¹H NMR (400 MHz, DMSO d₆) ppmδ 12.70 (s, 1H), 8.38 (s, 2H), 8.23-8.21 (m, 3H), 7.96 (s, 1H), 7.89 (s,1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 3.64 (s, 2H) 3.39-3.32(m, 3H), 2.36-2.29 (m, 4H), 2.19 (m, 3H); MS (ESI) m/z 462.5[C₂₇H₂₃N₇O+H]⁺.

Example 87:N-(4-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide

To a solution of (4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone (200 mg, 0.45 mmol) in acetonitrile (6mL) under inert atmosphere was added N-(4-ethynylpyridin-2-yl)acetamide(94.5 mg, 0.59 mmol), Pd(PPh₃)₄ (26.6 mg, 0.02 mmol), CuI (8.6 mg, 0.05mmol) and 3 mL of DIPEA. The reaction mixture was heated at 70° C. for2.5 h, was diluted with water (10 mL) and extracted with dichloromethane(20 mL×3). The combined organic layers were dried over sodium sulfatefiltered and concentrated under reduced pressure. The residue waspurified by flash column chromatography (silica gel, eluent,DCM/Methanol 94:6) to giveN-(4-((6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)pyridin-2-yl)acetamide(122 mg, 0.25 mmol, 57%, AUC HPLC 99.49%) as yellow solid mp:216.8-217.9° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44 (s, 1H), 8.28 (d,J=5.0 Hz, 1H), 8.15-8.05 (m, 4H), 7.96 (s, 1H), 7.64-7.60 (m, 3H), 7.22(dd, J=5.1, 1.3 Hz, 1H), 3.85 (bs, 2H), 3.52 (bs, 2H), 2.60-2.30 (m,7H), 2.25 (s, 3H); ¹³C NMR (400 MHz, CDCl₃) δ (ppm): 169.56, 168.79,151.81, 151.61, 147.78, 139.80, 139.36, 137.58, 136.29, 133.02, 127.96,127.39, 126.15, 121.26, 117.22, 115.44, 112.88, 96.87, 80.84, 46.01,24.76; MS (ESI) m/z 480.2 [C₂₇H₂₅N₇O₂+H]⁺.

Example 88:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone (180mg, 0.41 mmol) in acetonitrile (3 mL) was added 4-ethynylpyridin-2-amine(95.9 mg, 0.62 mmol), Pd(PPh₃)₄ (24.3 mg, 0.021 mmol), CuI (7.8 mg,0.041 mmol) and DIPEA (1.5 mL). The reaction mixture was heated at 85°C. for 1.5 h under nitrogen. The resulting mixture was diluted withdichloromethane (50 mL), filtered through celite and concentrated underreduced pressure. The residue was purified by flash columnchromatography (silica gel, 100% DCM to DCM/Methanol 96:4). Thefractions containing the products were concentrated under reducedpressure. The residue was diluted with DCM (50 mL) and washed withsaturated sodium bicarbonate solution (2×5 mL). The combined organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone(93 mg, 0.22 mmol, 53.4%, AUC HPLC 99.46%) as light yellow solid mp:143.5-144.2° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.22 (d, J=1.2 Hz, 1H),8.58 (d, J=1.2 Hz, 1H), 8.14 (d, J=4.8 Hz, 1H), 8.10-8.05 (m, 3H), 7.57(d, J=8.4 Hz, 2H), 6.83 (dd, J=5.2; 1.2 Hz, 1H), 6.69 (s, 1H), 4.61 (s,2H), 4.00-3.40 (m, 8H); MS (ESI) m/z 425.10 [C₂₄H₂₀N₆O₂+H]⁺.

Example 89:(4-methylpiperazin-1-yl)(4-(3-(phenylethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)methanone

To a solution of(4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(100 mg, 0.223 mmol), PdCl₂ (PPh₃)₂, (8 mg, 0.011 mmol), and CuI (4.2mg, 0.022 mmol) in THF (1 mL) was added phenyl acetylene (25 μL, 0.223mmol) and triethylamine (1 mL). The reaction mixture was stirred at roomtemperature for 12 h and was concentrated under reduced pressure. Theresidue was purified by flash chromatography to afford(4-methylpiperazin-1-yl)(4-(3-(phenylethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)methanoneas a light yellow solid (51 mg, 56%, AUC HPLC 98.19%). ¹H NMR (DMSO-d₆)δ (ppm): 9.29 (s, 1H), 9.09 (s, 1H), 8.28-8.21 (m, 3H), 7.81-7.76 (m,2H), 7.56-7.48 (m, 5H), 3.71-3.32 (m, 4H), 2.41-2.22 (m, 4H), 2.20 (s,3H). ¹³C NMR (DMSO-d₆) δ (ppm): 168.5, 142.5, 140.1, 139.8, 138.7,136.8, 136.1, 131.4, 129.4, 128.7, 127.4, 126.3, 121.4, 115.5, 110.0,100.2, 75.3, 54.2, and 45.5. MS (ESI): m/z 422 [C₂₆H₂₃N₅O+H]⁺.

Example 90:(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone (180mg, 0.41 mmol) in acetonitrile (3 mL) was added4-ethynyl-1H-pyrazolo[3,4-b]pyridine (88.04 mg, 0.62 mmol), Pd(PPh₃)₄(24.3 mg, 0.021 mmol), CuI (7.8 mg, 0.041 mmol) and DIPEA (1.5 mL). Thereaction mixture was heated at 80° C. overnight under nitrogen, was thendiluted with dichloromethane (50 mL), filtered through celite andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel, eluent DCM/Methanol 96:4) to yield(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone(77 mg, 0.17 mmol, 41.8%, AUC HPLC 98.87%) as yellow solid mp:192.8-193.8° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.31 (d, J=1.3 Hz, 1H),8.70 (d, J=1.3 Hz, 1H), 8.67 (d, J=4.7 Hz, 1H), 8.33 (s, 1H), 8.24 (s,1H), 8.10 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.41 (d, J=4.7 Hz,1H) 4.00-3.40 (m, 8H); MS (ESI) m/z 450.10 [C₂₅H₁₉N₇O₂+H]⁺.

Example 91:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-fluorophenyl)(morpholino)methanone

A round bottom flask was loaded with(2-fluoro-4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone(100 mg, 0.221 mmol), 4-ethynylpyridin-2-amine (39 mg, 0.332 mmol),PdCl₂(PPh₃)₂ (20 mg, 0.0287 mmol) and CuI (4.2 mg, 0.0221 mmol) followedby the addition of DMF (1.0 mL) and DIPEA (1.0 mL). The mixture washeated at 90° C. for 2 h under argon. The solvents were removed in vacuoand the crude residue was purified by column chromatography (silica gel,eluent EtOAc/CH₃OH 95:5) followed by preparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-fluorophenyl)(morpholino)methanone(42.9 mg, 44%, AUC HPLC: 99.0%) as a light brown solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 9.33 (d, J=1.5 Hz, 1H), 9.22 (d, J=1.5 Hz, 1H), 8.34(s, 1H), 8.14 (s, 1H), 8.13-8.10 (m, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.58(t, J=7.7 Hz, 1H), 6.90 (dd, J=5.5, 1.4 Hz, 1H), 6.86 (s, 1H), 6.69 (bs,2H), 3.68 (s, 4H), 3.56 (t, J=4.7 Hz, 2H) 3.35-3.25 (m, 2H); MS (ESI)m/z 443 [C₂₄H₁₉FN₆O₂+H]⁺

Example 92:(4-(3(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-fluorophenyl)(morpholino)methanone

The title compound was synthesized in a similar fashion as described forExample 91 starting from(4-(3-iodoimidazo[1,2-a]pyrazin-6-yl)-2-methylphenyl)(morpholino)methanoneand 4-ethynylpyridin-2-amine (40 mg, 0.335 mmol). The reaction crudeproduct was purified by column chromatography (silica gel, eluentEtOAc/CH₃OH 95:5) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-fluorophenyl)(morpholino)methanone(70.2 mg, 72%, AUC HPLC: 96.6%) as a brown solid. ¹H NMR (600 MHz,DMSO-d₆) δ (ppm): 9.33 (d, J=1.5 Hz, 1H), 9.14 (d, J=1.5 Hz, 1H), 8.35(s, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.06-8.01 (m, 2H), 7.35 (d, J=7.9 Hz,1H), 7.20 (bs, 2H), 7.01 (dd, J=5.9, 1.5 Hz, 1H), 6.99 (s, 1H), 3.68 (s,4H), 3.56-3.49 (m, 2H), 3.19 (s, 2H), 2.35 (s, 3H); MS (ESI) m/z 439[C₂₅H₂₂N₆O₂+H]⁺

Example 93:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-chlorophenyl)(morpholino)methanone

The title compound was synthesized in a similar fashion as described forExample 91 starting from(4-(3-bromoimidazo[1,2-a]pyrazin-6-yl)-2-chlorophenyl)(morpholino)methanone(55 mg, 0.13 mmol) and 4-ethynylpyridin-2-amine (40.2 mg, 0.26 mmol).The reaction crude product was purified by flash column chromatography(silica gel, eluent DCM/Methanol 96:4) and was washed with NaHCO₃ (2×5mL). The organic phase was dried over Na₂SO₄, filtered and concentratedto dryness under reduced pressure to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)-2-chlorophenyl)(morpholino)methanone(11.6 mg, 0.025 mmol, 19.4%, AUC HPLC 95.42%) as yellow solid mp:119.8-121.1° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.15 (s, 1H), 8.49 (s,1H), 8.07 (d, J=4.6 Hz, 1H), 8.02 (s, 2H), 7.87 (d, J=7.7 Hz, 1H), 7.38(d, J=7.7 Hz, 1H) 6.77 (d, J=4.6 Hz, 1H), 6.63 (s, 1H), 4.52 (s, 2H),3.90-3.80 (m, 1H), 3.79-3.70 (m, 3H), 3.69-3.50 (m, 2H), 3.35-3.15 (m,2H); MS (ESI) m/z 459.10 [C₂₄H₁₉ClN₆O₂+H]⁺.

Example 94:morpholino(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and4-iodopyridine in a similar method as described for Example 1. The crudeproduct was purified by flash column chromatography (silica gel, eluentCHCl₃/CH₃OH 95:5) to affordmorpholino(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone(40 mg, 32.5%, AUC HPLC 97.33%) as a pale yellow solid. m.p: 165-166°C.; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66 (s, 2H), 8.49 (s, 1H), 8.03(s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.73 (d, J=7.9 Hz, 2H), 7.51 (d, J=7.9Hz, 3H), 7.42 (s, 2H), 3.74 (s; 8H); MS (ESI) m/z 409.06[C₂₅H₂₀N₄O₂+H]⁺.

Example 95:(4-(3-((3-methylpyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and4-bromo-3-methylpyridine in a similar method as described for Example32. The crude product was purified by flash chromatography (silica gel,eluent CH₂Cl₂/CH₃OH 95:5) to afford(4-(3-((3-methylpyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(80 mg, 41.8%, LC-MS 97%, AUC HPLC 98.23%) as an off-white solid; m.p:99-104° C.; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.55-8.53 (m, 3H), 8.02 (s,1H), 7.82 (d, J=5.7 Hz, 1H), 7.71 (d, J=9.2 Hz, 2H), 7.52 (d, J=7.9 Hz,3H), 7.31 (d, J=4.8 Hz, 1H), 3.73-3.71 (m, 8H), 2.54 (s, 3H); MS (ESI)m/z 423.04 [C₂₆H₂₂N₄O₂+H]⁺.

Example 96:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

Step 1: Preparation of tert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-ylcarbamate:The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone andtert-butyl 4-bromopyridin-2-ylcarbamate in a similar method to thatdescribed for Example 32. The crude product was purified by flashchromatography (silica gel, eluent CHCl₃/CH₃OH 95:5) to affordtert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-ylcarbamate (90 mg, 57%, LC-MS 61%) as a solid.

Step 2: Preparation of(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone:The title compound was synthesized from tert-butyl4-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-ylcarbamatein a similar method as described in step 2 of Example 31 synthesis. Thecrude product was purified by flash column chromatography (silica gel,eluent CH₂Cl₂/CH₃OH 90:10) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(50 mg, 51.5%, AUC HPLC 97.57%) as a solid. m.p: 133-138° C.; ¹H NMR(400 MHz, CDCl₃) δ (ppm): 8.46 (s, 1H), 8.12 (d, J=5.3 Hz, 1H), 8.02 (s,1H), 7.79 (d, J=9.3 Hz, 1H), 7.61 (d, J=7.9 Hz, 2H), 7.56-7.54 (m, 3H),6.80 (s, 1H), 6.79 (s, 1H), 4.53 (s, 2H), 3.75-3.73 (m, 8H); MS (ESI)m/z 424.11 [C₂₅H₂₁N₅O₂+H]⁺

Example 97:(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

Step 1: Preparation of(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone:The title compound was prepared from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and4-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine in a similarmethod to that described for Example 1. The crude product was purifiedby flash chromatography (silica gel, eluent CHCl₃/CH₃OH 95:5) to afford(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(470 mg, 97%, LC-MS 85.3%) as a light yellow solid; ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.59 (d, J=4.8 Hz, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 8.16(s, 1H), 7.95 (bs, 1H), 7.68-7.57 (m, 6H), 7.34 (d, J=8.4 Hz, 2H), 6.84(d, J=8.4 Hz, 2H), 5.68 (s, 2H), 3.82-3.50 (m, 8H), 3.76 (s, 3H); MS(ESI) m/z 569.17 [C₃₄H₂₈N₆O₃+H]⁺

Step 2: Preparation of(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone:The title compound was synthesized from(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanoneby stirring with TFA at 100° C. for 4 h. The crude product (200 mg,LC-MS 78%) was purified by preparative HPLC to afford(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(25 mg, 9.6%, LC-MS 99%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃)δ (ppm): 10.97 (bs, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.57 (s, 1H), 8.27 (s,1H), 8.13 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 2H),7.63-7.59 (m, 3H), 7.33 (d, J=4.9 Hz, 1H), 3.82-3.55 (m, 8H); MS (ESI)m/z 449.04 [C₂₆H₂₀N₆O₂+H]⁺.

Example 98:(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and4-iodo-1H-indol-6-amine in a similar procedure to that described forExample 1. The crude material was purified by preparative HPLC (C18,eluent CH₃CN/H₂O/HCOOH 0.1%) to afford(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone (5 mg, 12%, AUC HPLC 95%) as a brown solid. ¹H NMR(400 MHz, CDCl₃) δ (ppm): 8.57 (s, 2H), 8.03 (s, 1H), 7.79 (d, J=9.3 Hz,1H), 7.69 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.1 Hz, 3H), 7.07 (s, 1H),6.58-6.54 (m, 2H), 4.39-4.30 (bs, 2H), 4.01-3.30 (m, 8H); ¹³C NMR (100MHz, CDCl₃) δ (ppm): 169.85, 154.56, 147.41, 145.33, 139.73, 138.72,135.13, 128.20, 127.32, 127.20, 126.36, 124.39, 122.69, 121.29, 118.65,113.24, 109.04, 104.86, 100.74, 96.98, 81.26, 66.92; MS (ESI) m/z 463[C₂₇H₂₂N₆O₂+H]⁺.

Example 99:(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and4-iodo-1H-pyrrolo[2,3-b]pyridine in a similar method to that describedfor Example 1. The reaction crude product was purified by preparativeHPLC (C18, eluent CH₃CN/H₂O/HCOOH 0.1%) to afford(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(8.8 mg, 22%, AUC HPLC 97%) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.60 (s, 1H), 8.34 (d, J=4.96 Hz, 1H), 8.06 (s, 1H), 7.81 (d,J=9.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.58 (q, J=3.6 Hz, 3H), 7.43 (t,J=2.8 Hz, 1H), 7.28-7.26 (m, 2H), 6.73-6.72 (m, 1H), 4.01-3.43 (m, 8H);¹³C NMR (100 MHz, CDCl₃) δ (ppm): 169.84, 148.44, 145.40, 142.99,139.88, 138.71, 135.16, 128.22, 127.32, 127.26, 126.44, 125.73, 122.69,122.38, 120.37, 118.30, 117.95, 109.00, 100.65, 96.85, 82.39, 66.92; MS(ESI) m/z 488 [C₂₇H₂₁N₅O₂+H]⁺.

Example 100:(4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

The title compound was synthesized from(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone and2-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine in a similar method to thatdescribed for Example 1. The residue was purified by preparative HPLC(C18, eluent CH₃CN/H₂O/HCOOH 0.1%) to afford (4-(3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(6.9 mg, AUC HPLC 95%) as a brown solid. ¹HNMR (400 MHz, CH₃OD) δ (ppm):8.74 (s, 1H), 8.35-8.32 (m, 1H), 8.05-8.00 (m, 2H), 7.87-7.77 (m, 4H),7.59 (d, J=8.3 Hz, 2H), 7.17 (q, J=4.2 Hz, 1H), 6.99 (s, 1H), 3.99 (s,3H), 3.89-3.48 (m, 8H); MS (ESI) m/z 462 [C₂₈H₂₃N₅O₂+H]⁺.

Example 101:N-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)acetamide

Step 1: Preparation of tert-butyl4-(4-(3-((2-acetamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate:The title compound was synthesized from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand N-(4-bromopyridin-2-yl)acetamide in a similar method to thatdescribed for Example 32. The crude product was purified by flashchromatography (silica gel, eluent CHCl₃/CH₃OH 90:10) to affordtert-butyl4-(4-(3-((2-acetamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(220 mg, LC-MS 40%) as an off-white solid.

Step 2: Preparation ofN-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)acetamide:The title compound was synthesized from tert-butyl4-(4-(3-((2-acetamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion to that described in step 2 of Example 45synthesis. The crude product was purified by preparative HPLC to affordN-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)acetamide(30 mg, AUC HPLC 96.5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 10.45 (s, 1H), 8.83 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.26 (s,2H), 8.19 (s, 1H), 7.90-7.13 (m, 4H), 7.53 (d, J=8.0 Hz, 2H), 7.40 (d,J=5.2 Hz, 1H), 3.57 (bs, 4H), 2.72 (bs, 4H), 2.12 (s, 3H); MS (ESI) m/z465.22 [C₂₇H₂₄N₆O₂+H]⁺.

Example 102:(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: Preparation of tert-butyl4-(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate:The title compound was synthesized starting from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand N-1-(4-iodopyridin-2-yl)-2-methylbenzene-1,3-diamine in a similarmethod to that described for Example 1. Water (2×100 mL) was added tothe reaction mixture to induce the desired product precipitation whichwas filtered to give crude product. The crude product was washed withn-hexane and dried to afford tert-butyl4-(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(230 mg, 78.8%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.42 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=9.2 Hz,1H), 7.66-7.53 (m, 5H), 7.06 (t, J=7.9 Hz, 1H), 6.80-6.78 (m, 2H), 6.63(d, J=7.9 Hz, 1H), 6.59 (s, 1H), 6.37 (s, 1H), 3.77 (bs, 4H), 3.48 (bs,6H), 2.09 (s, 3H), 1.48 (s, 9H); MS (ESI) m/z 628 [C₃₇H₃₇N₇O₃+H]⁺

Step 2: Preparation of(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone:The title compound was synthesized from tert-butyl4-(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion to that described for Example 45, step 2. The crudeproduct was purified by preparative HPLC to afford(4-(3-((2-(3-amino-2-methylphenylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone(80 mg, 41.4) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.43 (s, 1H), 8.18 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.75 (d, J=9.2 Hz,1H), 7.65-7.52 (m, 5H), 7.06 (t, J=7.9 Hz, 1H), 6.81-6.78 (m, 2H), 6.63(d, J=7.9 Hz, 1H), 6.59 (s, 1H), 6.36 (s, 1H), 3.76 (bs, 4H), 3.48 (bs,2H), 2.96-2.88 (m, 4H), 2.09 (s, 3H); MS (ESI) m/z 528.24[C₃₂H₂₉N₇O+H]⁺.

Example 103:(N-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)benzamide)

Step 1: Preparation of (tert-butyl4-(4-(3-((2-benzamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate):The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand N-(4-bromopyridin-2-yl)benzamide in a similar fashion to thatdescribed for Example 32. The crude product was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 98:2) to affordtert-butyl4-(4-(3-((2-benzamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(300 mg, 8.2%) as a pale yellow solid.

Step 2: Preparation of(N-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)benzamide):The title compound was prepared from (tert-butyl4-(4-(3-((2-benzamidopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate)in a similar fashion to that described in step 2 of Example 45synthesis. The crude product was purified by preparative HPLC to affordN-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)benzamide(20 mg, LC-MS 98%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.6 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.33 (d, J=5.3 Hz, 1H),8.04 (d, J=0.8 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.2 Hz, 1H),7.69 (d, J=7.4 Hz, 2H), 7.62-7.51 (m, 6H), 7.22 (d, J=5.3 Hz, 1H),3.77-3.73 (bs, 2H), 3.5 (bs, 2H), 2.94 (bs, 4H); MS (ESI) m/z 527.18[C₃₂H₂₆N₆O₂+H]⁺.

Example 104:(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: Preparation of (tert-butyl4-(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate).The title compound was prepared starting from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine in a similarfashion as described for Example 1. The crude product was washed withn-hexane and dried to afford tert-butyl4-(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(320 mg, 58.9%) as a yellow solid. ¹H NMR (400 MHz, DMSO d₆) δ (ppm):8.95 (s, 1H), 8.65 (d, J=4.9 Hz, 1H), 8.46 (s, 1H), 7.94-7.89 (m, 4H),7.59-7.54 (m, 3H), 7.48-7.45 (m, 2H), 7.25 (d, J=8.3 Hz, 2H), 6.87 (d,J=8.3 Hz, 2H), 5.64 (s, 2H), 3.7 (s, 3H), 3.6-3.35 (m, 8H), 1.41 (s,9H); MS (ESI) m/z 668.3 [C₃₉H₃₇N₇O₄+H]⁺.

Step 2: Preparation of(N-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)benzamide):The title compound was prepared in a similar fashion as in step 2 ofExample 97 synthesis. The crude product (180 mg, LC-MS 58%) was purifiedby preparative HPLC to afford(4-(3-((1H-pyrazolo[3,4-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone(30 mg, 37.3%, LC-MS 97.7%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 13.91 (bs, 1H), 8.91 (s, 1H), 8.59 (d, J=4.8 Hz, 1H),8.43 (s, 1H), 8.27 (s, 1H), 7.92-7.84 (m, 4H), 7.55-7.50 (m, 3H), 3.56(bs, 2H), 3.4 (bs, 2H), 2.71-2.67 (m, 4H); MS (ESI) m/z 446.4[C₂₆H₂₁N₇O+H]⁺.

Example 105:piperazin-1-yl(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone

Step 1: Preparation of tert-butyl4-(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate:The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-bromo-N-(pyridin-3-yl)pyridin-2-amine in a similar fashion asdescribed for Example 32. The crude product was purified by flash columnchromatography (silica gel, eluent CHCl₃/CH₃OH 97:3) to affordtert-butyl4-(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(200 mg, 14.7%) as a brown solid.

Step 2: Preparation ofpiperazin-1-yl(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone:The title compound was prepared from tert-butyl4-(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(200 mg, 0.33 mmol) in a similar fashion as in step 2, of Example 45synthesis. The crude product was purified by preparative HPLC to affordpiperazin-1-yl(4-(3-((2-(pyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone(25 mg, 15%, AUC HPLC 96.8%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 9.40 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 8.25-8.13(m, 4H), 7.93-7.82 (m, 4H), 7.6 (d, J=7.9 Hz, 2H), 7.32-7.29 (m, 1H),7.06 (s, 2H), 3.64-3.4 (bs, 4H), 3.05 (bs, 4H); MS (ESI) m/z 500.1[C₃₀H₂₅N₇O+H]⁺.

Example 106:piperazin-1-yl(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone

Step 1: Preparation of (tert-butyl4-(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate):The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-iodo-N-(o-tolyl)pyridin-2-amine in a similar fashion as describedfor Example 1. The crude product was purified by flash columnchromatography (silica gel, eluent CHCl₃/CH₃OH 98:2) to affordtert-butyl4-(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(190 mg, 68.5%, LC-MS 90%) as a pale yellow solid.

Step 2: Preparation of(piperazin-1-yl(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone):The title compound was prepared from tert-butyl4-(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2, Example 45. The crude product waspurified by column chromatography (silica gel, eluent MeOH/DCM 10:90)and by preparative HPLC to affordpiperazin-1-yl(4-(3-((2-(o-tolylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone(50 mg, 33.3%, AUC HPLC 98%) as a pale yellow solid. ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.44 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.76(d, J=9.2 Hz, 1H), 7.65-7.53 (m, 5H), 7.44 (d, J=7.9 Hz, 1H), 7.29-7.23(m, 2H), 7.15-7.13 (m, 1H), 6.84 (d, J=4.8 Hz, 1H), 6.74 (s, 1H), 6.37(s, 1H), 3.8 (bs, 2H), 3.5 (bs, 2H), 2.94-2.84 (m, 4H), 2.30 (s, 3H); MS(ESI) m/z 513.13 [C₃₂H₂₈N₆O+H]⁺.

Example 107:N-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)acetamide

Step 1: Preparation of (tert-butyl4-(4-(3-((2-(2-methylpyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate):The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-bromo-N-(2-methylpyridin-3-yl)pyridin-2-amine in a similar fashionas described for Example 32. The crude product was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 97:3) to affordtert-butyl 4-(4-(3-((2-(2-methylpyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate (160mg, 74.8%, LC-MS 68%) as a yellow solid.

Step 2: Preparation of((4-(3-((2-(2-methylpyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone):The title compound was prepared from tert-butyl4-(4-(3-((2-(2-methylpyridin-3-ylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2, Example 45. The crude product (140 mg,LC-MS 70.7%) was purified by preparative HPLC to affordN-(4-((6-(4-(piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)pyridin-2-yl)acetamide(20 mg, 15.9%, AUC HPLC 98.51%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.45 (s, 1H), 8.32 (d, J=3.9 Hz, 1H), 8.24 (d, J=5.2 Hz,1H), 7.99 (s, 1H), 7.78 (d, J=9.7 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H),7.56-7.52 (m, 3H), 7.28-7.19 (m, 1H), 6.92 (d, J=5.3 Hz, 1H), 6.76 (s,1H), 6.29 (s, 1H), 3.8 (bs, 2H), 3.48 (bs, 2H), 2.98-2.86 (m, 4H), 2.57(s, 3H); MS (ESI) m/z 512.4 [C₃₁H₂₇N₇O—H]⁺.

Example 108:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: Preparation of (tert-butyl4-(4-(3-((2-(tert-butoxycarbonylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate):The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand tert-butyl (4-bromopyridin-2-yl)carbamate in a similar fashionExample 32. The crude product was purified by column chromatography(silica gel, eluent CHCl₃/CH₃OH 97:3) to afford tert-butyl4-(4-(3-((2-(tert-butoxycarbonylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(210 mg, 48%, LC-MS 55%) as a solid.

Step 2: Preparation of(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone):The title compound was prepared from tert-butyl4-(4-(3-((2-(tert-butoxycarbonylamino)pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2, Example 45. The crude product (130 mg,LC-MS 26%) was purified by preparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone(20 mg, 14%, AUC HPLC 97%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.46 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 7.99 (s, 1H), 7.78 (d,J=9.2 Hz, 1H), 7.67-7.65 (m, 2H), 7.57-7.52 (m, 3H), 6.80 (d, J=4 Hz,1H), 6.65 (s, 1H), 4.50 (bs, 2H), 3.80 (bs, 2H), 3.48 (bs, 2H),2.96-2.87 (m, 4H); MS (ESI) m/z 423.17 [C₂₅H₂₂N₆O+H]⁺.

Example 109:piperazin-1-yl(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone

Step 1: Preparation of tert-butyl4-(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate:The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-iodopyridine in a similar fashion as Example 1. The crude productwas purified by flash chromatography (silica gel, eluent CHCl₃/CH₃OH90:10) afforded tert-butyl4-(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(80 mg, 68%, LC-MS 93%) as a solid.

Step 2: Preparation ofpiperazin-1-yl(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone:The title compound was prepared from tert-butyl4-(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as described in step 2 of Example 45 synthesis. Thecrude product was purified by flash column chromatography (silica gel,eluent CH₂Cl₂/CH₃OH 90:10) to affordpiperazin-1-yl(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)methanone,(30 mg, 46.8%, AUC HPLC 97.88%) as a light brown solid; m.p: 125-130° C.¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.60 (d, J=4.4 Hz, 2H), 8.48 (s, 1H),8.02 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.61 (d, J=7.4 Hz, 2H), 7.50 (d,J=7.9 Hz, 3H), 7.42 (d, J=4.8 Hz, 2H), 3.79 (s, 2H), 3.48 (s, 2H), 2.88(s, 4H); MS (ESI) m/z 408.25 [C₂₅H₂₁N₅O+H]⁺.

Example 110:(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: Preparation of tert-butyl4-((6-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate:The title compound was prepared from tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand tert-butyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate in asimilar fashion as described for Example 32. The crude product waspurified by flash chromatography (silica gel, eluent CHCl₃/CH₃OH 90:10)to afford tert-butyl4-((6-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(350 mg, 51%, LC-MS 91.6%) as a pale yellow solid.

Step 2: Preparation of tert-butyl4-((6-(4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate:The title compound was prepared from tert-butyl4-(4-(3-(pyridin-4-ylethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2 of Example 45 synthesis. The reactionmixture was concentrated and basified with NaHCO₃, diluted with EtOAcand washed in turn with water and brine solution. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toobtain crude product. The crude product was purified by flash columnchromatography (silica gel, eluent CHCl₃/CH₃OH 90:10) and by preparativeHPLC to afford to afford(4-(3-((1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone(70 mg, 29%, AUC HPLC 98.53%) as a pale yellow solid; m.p: 242-245° C.;¹H NMR (400 MHz, DMSO d₆) δ (ppm): 11.94 (s, 1H), 8.82 (s, 1H), 8.27 (d,J=4.8 Hz, 2H), 8.20 (s, 1H), 7.90-7.82 (m, 4H), 7.64 (s, 1H), 7.53 (d,J=8.4 Hz, 2H), 7.38 (d, J=4.8 Hz, 1H), 6.71 (s, 1H), 3.75 (bs, 4H), 2.67(bs, 4H); MS (ESI) m/z 447.08 [C₂₇H₂₂N₆O+H]⁺.

Example 111:(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone

Step 1: Preparation of tert-butyl4-(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate:The title compound was prepared from (tert-butyl4-(4-(3-ethynylimidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylateand 4-iodo-1H-indol-6-amine in a similar fashion as Example 1. The crudeproduct was purified by preparative HPLC (C18, eluent CH₃CN/H₂O/HCOOH0.1%) to afford tert-butyl4-(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylate(16 mg, 25%, AUC HPLC 99%) as a brown solid. ¹H NMR (400 MHz, CH₃OD) δ(ppm): 8.74 (s, 1H), 8.03 (s, 1H), 7.91-7.60 (m, 4H), 7.61 (d, J=8.2 Hz,2H), 7.07 (d, J=3.4 Hz, 1H), 6.63 (s, 1H), 6.45 (d, J=3.5 Hz, 1H), 4.54(s, 1H), 3.81-3.51 (m, 8H), 1.47 (s, 9H); MS (ESI) m/z 562[C₃₂H₃₁N₇O₂+H]⁺.

Step 2: Preparation of(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone:The title compound was prepared from tert-butyl4-(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2 of Example 45. The reaction mixture waspurified by preparative HPLC (C18, eluent CH₃CN/H₂O/HCOOH 0.1%) toafford(4-(3-((6-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(piperazin-1-yl)methanone(14 mg, 100%, AUC HPLC 99%) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.26 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 7.94-7.83 (m, 4H),7.64 (d, J=8.2 Hz, 2H), 7.11 (s, 1H), 6.58 (s, 1H), 6.47 (s, 1H),4.20-3.11 (m, 8H); ¹³C NMR (100 MHz, DMSO-d₆) δ (ppm): 168.72, 137.65,134.41, 128.03, 127.01, 122.88, 117.51, 111.23, 103.95, 42.59; MS (ESI)m/z 462 [C₂₇H₂₃N₇O₂+H]⁺.

Example 112:(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-iodoimidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone (500mg, 1.15 mmol) and diisopropylethylamine (0.62 mL, 3.46 mmol) in DMF (15mL) under argon were successively added Pd(PPh₃)₄ (66.6 mg, 0.0 mmol),PPh₃ (14.9 mg, 0.057 mmol), CuI (32.8 mg, 0.173 mmol) and5-ethynyl-1H-benzo[d]imidazole (196 mg, 1.38 mmol), the reaction mixturewas heated at 80° C. for 10 h. The reaction mixture was poured intoice-water, extracted with ethyl acetate. The organic layer was washed inturn with water and brine, was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to afford(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(morpholino)methanone(300 mg, 58.8%, HPLC 98%) as an off-white solid. ¹H NMR (400 MHz,(DMSO-d₆) δ (ppm): 12.68 (s, 1H), 8.80 (s, 1H), 8.33 (S, 1H), 8.05-7.84(m, 4H), 7.82-7.49 (m, 6H), 3.62-3.28 (m, 8H); MS (ESI) m/z: 448.08[C₂₇H₂₁N₅O₂+H]⁺.

Example 113:(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone

To a solution of(4-(3-iodo-3aH-pyrrolo[3,2-b]pyridin-5-yl)phenyl)(4-methylpiperazin-1-yl)methanone(800 mg, 1.79 mmol) and diisopropylethylamine (0.64 mL, 3.58 mmol) inDMF (05 mL) were successively added Pd(PPh₃)₄ (103 mg, 0.0896 mmol),PPh₃ (23.4 mg, 0.0896 mmol), CuI (51 mg, 0.268 mmol) and5-ethynyl-1H-benzo[d]imidazole (254 mg, 1.79 mmol). The reaction mixturewas heated at 80° C. for 10 h under argon. and was poured into icewater, extracted with ethyl acetate. The organic layer was washed inturn with water and brine, was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to afford(4-(3-((1H-benzo[d]imidazol-5-yl)ethynyl)imidazo[1,2-a]pyridin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(220 mg, 26.6%, HPLC 98%) as pale yellow solid. ¹H NMR (400 MHz,(DMSO-d₆) δ (ppm): 8.77 (s, 1H), 8.24 (s, 1H), 8.03 (S, 2H), 7.95 (s,1H), 7.87 (d, J=14 Hz, 2H), 7.84-7.77 (m, 2H), 7.65 (d, J=8.4 Hz, 1H),7.55 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 3.42-3.39 (m, 4H),2.37-2.32 (m, 4H), 2.20 (s, 3H); MS (ESI) m/z: 461.45 [C₂₈H₂₄N₆O+H]⁺.

Example 114:morpholino(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone

Step 1: Preparation of ethyl 4-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoate:A mixture of 4-(ethoxycarbonyl)phenylboronic acid (6.08 g, 31.37 mmol),K₃PO₄ (11 g, 52.28 mmol), Pd(PPh₃)₄ (0.4 g) and5-chloropyrazolo[1,5-a]pyrimidine (4 g, 26.14 mmol) in a mixture of1,4-dioxane (250 mL) and H₂O (50 mL) was stirred at room temperature.The reaction mixture was refluxed overnight under argon and the reactionmixture was diluted with EtOAc and washed in turn with water and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give the crude product which was purified by flashcolumn chromatography (silica gel, eluent petroleum ether/EtOAc 50:50)to afford ethyl 4-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (3.6 g, 52%,LC-MS 95%) as a yellow solid.

Step 2: Preparation of ethyl4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)benzoate: To a solution of ethyl4-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoate 1 (3.6 g, 13.48 mmol) in ACN(60 mL) was added NIS (3.6 g, 16.17 mmol) at 0° C. to room temperatureand stirred at the same temperature for 3 h. The restion mixture wasdiluted with water (100 mL) and filtered. The filtrate was washed withwater to afford ethyl 4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)benzoate(4.6 g, 88%, LC-MS 99%) as a yellow solid.

Step 3: Preparation of ethyl4-(3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate: Amixture of ethyl 4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)benzoate (4.6 g,11.7 mol), ethynyltrimethylsilane (1.37 g, 14.04 mmol), CuI (725 mg,3.81 mmol), and DIPEA (2.26 g, 17.5 mol) was stirred under argon for 30min prior to the addition of Pd(PPh₃)₄. The reaction mixture was heatedat 80° C. for 4 h, was diluted with Water (100 mL). The precipitate wasisolated by filtration and purified by flash chromatography (silica gel,eluent petroleum ether/EtOAc 50:50) to afford ethyl4-(3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate(3.6 g, 85%, LC-MS 95%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.25-8.23 (m, 5H), 7.38 (d, J=7.6 Hz, 2H), 4.4 (q, 2H), 1.43 (t,J=7.6 Hz, 3H), 0.31 (s, 9H); MS (ESI) m/z 364 [M+1]⁺.

Step 4: Preparation of 4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoicacid: To a solution ofethyl-4-(3-(trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate(1.8 g, 4.95 mmol) in THF (15 mL) was added LiOH (0.62 g, 14.87 mmol) inwater (3 mL) and MeOH (5 mL) and stirred for 4 h at room temperature.The reaction mixture was concentrated under reduced pressure to afford4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (1.2 g, 92%) as alight brown solid; ¹H NMR (400 MHz, CDCl₃) δ (ppm): 13.20 (s, 1H), 9.32(d, J=6.8 Hz, 1H), 8.45 (m, 3H), 8.12 (s, 2H), 7.83 (d, J=7.6 Hz, 1H),4.32 (s, 1H); MS (ESI) m/z 264 [M+1].

Step 5: Preparation of(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone:To a solution of 4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid(0.6 g, 2.28 mmol) in DMF (6 mL) was added NMM (0.46 g, 4.56 mmol)followed by HATU (1.3 g, 3.42 mmol) and the mixture was stirred at roomtemperature for 30 min prior to the addition of morpholine (0.23 g, 2.73mmol). The reaction mixture was stirred at room temperature forovernight, was diluted with EtOAc and washed in turn with water andbrine solution. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 96.5:3.5) to afford(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(0.45 g, 51%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.72(d, J=7.2 Hz, 1H), 8.25-8.22 (m, 3H), 7.55 (d, J=8.0 Hz, 2H), 7.41 (d,J=7.6 Hz, 1H), 3.60 (s, 6H), δ 3.55 (s, 1H), 3.50 (s, 2H); MS (ESI) m/z333 [M+1].

Step 6: Preparation ofmorpholino(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone:The title compound was synthesized from(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanoneand 4-iodopyridine in a similar fashion as described for Example 1. Thecrude product was purified by flash chromatography to affordmorpholino(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone(80 mg, 44%, AUC HPLC 96.38%) as an yellow solid: m.p. 206-209° C. ¹HNMR (400 MHz, CDCl₃) δ (ppm): 8.75 (d, J=7.2 Hz, 1H), 8.62 (d, J=5.6 Hz,2H), 8.34 (s, 1H), 8.26 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H),7.47-7.40 (m, 3H), 3.82-3.65 (m, 8H); MS (ESI) m/z 410.07[C₂₄H₁₉N₅O₂+H]⁺.

Example 115:piperazin-1-yl(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone

Step 1: Preparation of tert-butyl4-(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylate:To a solution of 4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid(0.3 g, 1.14 mmol) in DMF (6 mL) was added NMM (0.23 g, 2.28 mmol)followed by HATU (0.65 g, 1.71 mmol) at room temperature and stirred for30 min prior to the addition of tert-butyl piperazine-1-carboxylate(0.25 g, 1.36 mmol). The reaction mixture was stirred at roomtemperature overnight, was diluted with EtOAc and washed in turn withwater and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica gel, eluent CHCl₃/CH₃OH 96.5:3.5) toafford tert-butyl4-(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylate(0.3 g, 61% as a yellow solid.

Step 2: Preparation of tert-butyl4-(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylate:The title compound was synthesized from tert-butyl4-(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylateand 4-iodopyridine in a similar fashion as Example 1. The crude productwas purified by flash chromatography (silica gel, eluent CH₂Cl₂/CH₃OH10:90) to afford tert-butyl4-(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylate(200 mg, 57%) as a yellow solid.

Step 3: Preparation ofpiperazin-1-yl(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone:The title compound was synthesized from tert-butyl4-(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoyl)piperazine-1-carboxylatein a similar fashion as step 2, Example 45. The crude product waspurified by column chromatography (silica gel, eluent CH₂Cl₂/CH₃OH90:10) to affordpiperazin-1-yl(4-(3-(pyridin-4-ylethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)methanone(60 mg, 44%, AUC HPLC 98.4%) as a yellow solid. m.p. 120-136° C. ¹H NMR(400 MHz, CDCl₃) δ (ppm): 8.74 (d, J=7.6 Hz, 1H), 8.62 (d, J=5.2 Hz,2H), 8.33 (s, 1H), 8.25 (d, J=7.6 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H),7.46-7.40 (m, 3H), 3.80 (bs, 2H), 3.44 (bs, 2H), 2.86 (bs, 2H); MS (ESI)m/z 409.06 [C₂₄H₂₀N₆O+H]⁺.

Example 116:(4-(3-((3-methylpyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone

Step 1: Preparation of(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone:To a solution of 4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid(0.6 g, 2.28 mmol) in DMF (6 mL) was added NMM (0.46 g, 4.56 mmol)followed by HATU (1.3 g, 3.42 mmol) at room temperature and stirred for30 min prior to the addition of morpholine (0.23 g, 2.73 mmol). Thereaction mixture was stirred at room temperature overnight, was dilutedwith EtOAc and washed in turn with water and brine solution. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give the crude product which was purified by columnchromatography (silica gel, eluent CHCl₃/CH₃OH 96.5:3.5) to afford(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(0.45 g, 51% as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.70(d, J=7.2, 1H), 8.25-8.22 (m, 3H), 7.55 (d, J=8.0, 2 H), 7.40 (d, J=7.6,1H), 3.55 (s, 1H), 3.60-4.00 (m, 6H), 3.50 (bs, 2H); MS (ESI) m/z 333[C₁₉H₁₆N₄O₂+H]⁺.

Step 2: Preparation of(4-(3-((3-methylpyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone:The title compound was synthesized from(4-(3-ethynylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanoneand 4-bromo-3-methyl pyridine in a similar fashion as Example 32. Thecrude product was purified by flash chromatography (silica gel, eluentCH₂Cl₂/CH₃OH 90:10) to afford(4-(3-((3-methylpyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(35 mg, 16%, AUC HPLC 98.63%) as a yellow solid. m.p. 233-236° C. ¹H NMR(400 MHz, CDCl₃) δ (ppm): 8.75 (d, J=7.2 Hz, 1H), 8.52 (s, 2H), 8.42 (s,1H), 8.21-8.4 (m, 3H), 7.60 (d, J=7.6 Hz, 2H), 7.41 (d, J=6.8 Hz, 1H),3.8-3.40 (m, 8H), 2.58 (s, 3H); MS (ESI) m/z 409.06 [C₂₄H₂₀N₆O+H]⁺.

Example 117:(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5yl)phenyl)(morpholino)methanone

To a solution of(4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(150 mg, 0.35 mmol) in anhydrous acetonitrile (6 mL) was added4-ethynylpyridin-2-amine (71.13 mg, 0.46 mmol), Pd(PPh₃)₄ (20.22 mg,0.018 mmol), CuI (6.67 mg, 0.035 mmol) and 3 mL of DIPEA. The reactionmixture was heated at 75° C. under nitrogen overnight, was diluted withDCM (100 mL), filtered through celite and concentrated under reducedpressure. The residue was purified by flash column chromatography(silica gel, eluent DCM/Methanol 96:4) to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5yl)phenyl)(morpholino)methanone (59.38 mg, 0.14 mmol, 40%, AUC HPLC97.07%) as yellow solid mp: 129.8-130.6° C. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.74 (d, J=7.3 Hz, 1H), 8.31 (s, 1H), 8.25 (d, J=8.2 Hz, 2H),8.06 (d, J=5.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.3 Hz, 1H),6.84 (d, J=5.2 Hz, 1H), 6.71 (s, 1H), 4.55 (bs, 2H), 4.00-3.30 (m, 8H);¹³C NMR (400 MHz, CDCl₃) δ (ppm): 169.61, 158.25, 156.56, 148.67,148.25, 147.88, 137.84, 137.70, 136.05, 133.29, 127.88, 116.08, 110.27,106.45, 93.81, 91.43, 83.35, 66.88; MS (ESI) m/z 425.20 [C₂₄H₂₀N₆O₂+H]⁺.

Example 118:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone

To a solution of(4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-2-(trifluoromethyl)phenyl)(morpholino)methanone(180 mg, 0.36 mmol) in anhydrous acetonitrile (3 mL) was added4-ethynylpyridin-2-amine (83.5 mg, 0.54 mmol), Pd(PPh₃)₄ (20.80 mg,0.018 mmol), CuI (6.86 mg, 0.036 mmol) and 1.5 mL of DIPEA. The reactionmixture was heated under nitrogen at 85° C. for 1.5 h, was then dilutedwith 100 mL of DCM, filtered through celite and concentrated underreduced pressure. The residue was purified by flash columnchromatography (silica gel, eluent DCM/Methanol 96:4) to give(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-chlorophenyl)(morpholino)methanone(141.2 mg, 0.29 mmol, 79.7%, AUC HPLC 99.33%) as yellow-orange solid mp:247.8-248.3° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.79 (d, J=7.4 Hz, 1H),8.52 (s, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.34 (s, 1H), 8.07 (d, J=5.2 Hz,1H), 7.53 (d, J=8.0 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 6.83 (d, J=5.2 Hz,1H), 6.71 (s, 1H), 4.55 (bs, 2H), 4.00-3.85 (m, 1H), 3.84-3.70 (m, 3H),3.69-3.50 (m, 2H), 3.30-3.15 (m, 2H); MS (ESI) m/z 493.10[C₂₅H₁₉F₃N₆O₂+H]⁺.

Example 119:(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylphenyl)(morpholino)Methanone

To a solution of(4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-2-methylphenyl)(morpholino)methanone (100 mg, 0.223 mmol), 4-ethynylpyridin-2-amine hydrochloride(42 mg, 0.268 mmol), PdCl₂(PPh₃)₂ (20 mg, 0.0290 mmol), CuI (4 mg,0.0223 mmol) in a mixture of DMF and THF (1:3, 2.0 mL) was added Et₃N(2.0 mL). The resulting mixture was stirred at room temperature for 12h. The solvents were removed in vacuo and the residue was purified byflash column chromatography (eluent EtOAc/CH₃OH 85:15) followed bypreparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylphenyl)(morpholino)methanone (29.9 mg, 31%, AUC HPLC 99.2%) as a yellow solid. ¹H NMR (600MHz, DMSO-d₆) δ 9.30 (d, J=7.4 Hz, 1H), 8.55 (s, 1H), 8.19 (d, J=1.8 Hz,1H), 8.17-8.11 (m, 1H), 7.94 (d, J=5.3 Hz, 1H), 7.83 (d, J=7.4 Hz, 1H),7.41 (d, J=8.0 Hz, 1H), 6.64-6.56 (m, 2H), 6.11 (s, 2H), 3.68 (m, 4H),3.52 (m, 2H), 3.18 (m, 2H), 2.36 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ168.0, 159.8, 156.5, 148.1, 147.8, 138.5, 137.4, 136.2, 134.8, 131.3,129.2, 126.6, 125.1, 113.1, 109.0, 107.1, 91.8, 91.1, 83.2, 66.2, 46.7,18.7; MS (ESI) m/z 439 [C₂₅H₂₂N₆O₂+H]⁺

Example 120:(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-chlorophenyl)(morpholino)methanone

To a solution of(2-chloro-4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(180 mg, 0.38 mmol) in anhydrous acetonitrile (3 mL) was added4-ethynylpyridin-2-amine (89 mg, 0.58 mmol), Pd(PPh₃)₄ (21.96 mg, 0.019mmol), CuI (7.24 mg, 0.038 mmol) and 1.5 mL of DIPEA. The reactionmixture was heated at 85° C. for 1.5 h under nitrogen. The reactionmixture was diluted with 100 mL of DCM, filtered through celite andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel, eluent DCM/Methanol 96:4) to give(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-chlorophenyl)(morpholino)methanone(159.4 mg, 0.35 mmol, 91%, AUC HPLC 99.53%) as yellow solid mp:218.5-219.6° C. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.77 (d, J=7.4 Hz, 1H),8.35 (s, 1H), 8.29 (d, J=1.2 Hz, 1H), 8.14 (dd, J=8.0, 1.2 Hz, 1H), 8.10(d, J=5.2 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 6.86(d, J=5.2 Hz, 1H), 6.73 (s, 1H), 4.52 (s, 2H), 4.00-3.85 (m, 1H),3.84-3.80 (m, 3H), 3.79-3.55 (m, 2H), 3.45-3.15 (m, 2H); ¹³C NMR (400MHz, CDCl₃) δ (ppm): 166.28, 158.32, 155.15, 148.45, 148.17, 138.79,137.51, 136.24, 133.03, 131.47, 128.77, 128.56, 126.35, 116.11, 110.19,106.20, 94.16, 91.64, 82.90, 66.79, 66.73, 47.17, 42.17; MS (ESI) m/z459.10 [C₂₄H₁₉ClN₆O₂+H]⁺.

Example 121:(4-(3-((2-aminothiazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone

Step 1: Preparation of tert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)thiazol-2-ylcarbamate.To a solution of(4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (300mg, 0.691 mmol) in DMF (10 mL) were successively added Pd(PPh₃)₄ (40 mg,0.03 mmol), CuI (19.6 mg, 0.11 mmol), N,N-diisopropylethylamine (0.23mL, 1.38 mmol) and tert-butyl 5-ethynylthiazol-2-ylcarbamate (185 mg,0.82 mmol). The reaction mixture was heated at 80° C. for 5 h underargon, was filtered through celite and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (Silica gel, eluent dichloromethane/MeOH 9:1) to affordtert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)thiazol-2-ylcarbamate(300 mg). ¹H NMR (400 MHz, (DMSO-d₆) δ (ppm): 11.94 (s, 1H), 8.35 (d,J=9.2 Hz, 1H), 8.23-8.00 (m, 3H), 7.96 (d, J=12.8 Hz, 1H), 7.84 (s, 1H),7.62 (d, J=8.0 Hz, 2H), 3.63-3.60 (bs, 8H), 1.52 (s, 9H). MS (ESI) m/z:531.60 [C₂₇H₂₆N₆O₄S+H]⁺.

Step 2: Preparation of(4-(3-((2-aminothiazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone.A solution of tert-butyl5-((6-(4-(morpholine-4-carbonyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)thiazol-2-ylcarbamate(300 mg, 0.56 mmol) in a mixture of trifluoroacetic acid (3 mL) anddichloromethane (10 mL) was stirred at room temperature for 3 h. Thereaction mixture was concentrated under reduced pressure and the residuewas basified with a saturated aqueous solution of NaHCO₃, extracted witha solution of 10% methanol in dichloromethane. The organic layer waswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to afford(4-(3-((2-aminothiazol-5-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(60 mg, 25%, AUC HPLC 98.69%) as a yellow solid. mp 245-254° C.; ¹H NMR(400 MHz, (DMSO-d₆) δ (ppm): 8.33 (d, J=9.6 Hz, 1H), 8.18-8.17 (m, 3H),7.97 (d, J=9.2 Hz, 1H), 7.62-7.61 (m, 4H), 7.44 (s, 1H), 3.64-3.62 (m,8H); MS (ESI) m/z: 431.11 [C₂₂H₁₈N₆O₂S+H]⁺.

Example 122:(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-3-fluorophenyl)(morpholino)methanoneFormate Salt

A solution of(3-fluoro-4-(3-iodoimidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone(92 mg, 0.203 mmol), 4-ethynylpyridin-2-amine (36 mg, 0.305 mmol),PdCl₂(PPh₃)₂ (19 mg, 0.0264 mmol), CuI (4 mg, 0.0203 mmol) in a mixtureof DMF (1.0 mL) and (1.0 mL). The mixture was blanketed with argon andheated at 90° C. for 2 h. The solvents were removed in vacuo and thecrude residue was purified by column chromatography (silica gel, eluentEtOAc/CH₃OH 90:10) and preparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)-3-fluorophenyl)(morpholino)methanoneformate salt (40.0 mg, 40%, AUC HPLC: 97.2%) as a green-brown solid mp:78.2-79.4° C.); ¹H NMR (600 MHz, DMSO-d₆) δ 8.37 (d, J=9.5 Hz, 1H), 8.31(s, 1H), 8.13 (s, 1H), 8.00-7.93 (m, 2H), 7.75 (dd, J=9.4, 2.1 Hz, 1H),7.54 (dd, J=10.9, 1.5 Hz, 1H), 7.47 (dd, J=7.9, 1.6 Hz, 1H), 6.64 (d,J=4.9 Hz, 2H), 6.33 (s, 2H), 3.71-3.62 (m, 4H), 3.62-3.52 (m, 4H); ¹³CNMR (150 MHz, DMSO-d₆) δ 167.00, 163.06, 160.36, 159.40, 158.69, 149.05,147.57, 139.76, 138.97, 131.27, 130.48, 126.22, 124.29, 123.72, 115.46,112.80, 111.70, 109.41, 96.90, 79.05, 66.01, 47.62, 42.06; MS (ESI) m/z443 [C₂₄H₁₉FN₆O₂+H]⁺.

Example 123:(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-fluorophenyl)(morpholino)Methanone Formic Acid Salt

A solution of(3-fluoro-4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)phenyl)(morpholino)methanone(89 mg, 0.197 mmol), 4-ethynylpyridin-2-amine (35 mg, 0.295 mmol),PdCl₂(PPh₃)₂ (20 mg, 0.0256 mmol), CuI (4 mg, 0.0197 mmol) in a mixtureof DMF (1.0 mL) and DIPEA (1.0 mL) was heated at 90° C. for 2 h. Thesolvents were removed in vacuo and the crude residue was purified bycolumn chromatography (silica gel, eluent EtOAc/CH₃OH 95:5) and bypreparative HPLC to afford(4-(3-((2-aminopyridin-4-yl)ethynyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-fluorophenyl)(morpholino) methanone formic acid salt (54.8 mg, 57%, AUC HPLC: 98.0%)as a brown solid (mp: 57.6-58.9° C.); ¹H NMR (600 MHz, DMSO-d₆) δ 9.33(d, J=7.3 Hz, 1H), 8.62 (s, 1H), 8.17-8.10 (m, 2H), 7.93 (d, J=5.5 Hz,1H), 7.59 (dd, J=7.4, 1.8 Hz, 1H), 7.52 (d, J=11.2 Hz, 1H), 7.46 (d,J=7.8 Hz, 1H), 6.69-6.62 (m, 2H), 6.50 (s, 2H), 3.74-3.62 (m, 4H),3.62-3.53 (m, 4H); ¹³C NMR (150 MHz, DMSO-d₆) δ 166.98, 163.06, 160.80,159.13, 158.55, 153.76, 148.19, 145.75, 139.95, 137.31, 132.55, 131.33,125.69, 123.66, 115.54, 113.11, 110.36, 110.05, 91.98, 91.00, 66.01,47.56, 42.06; MS (ESI) m/z 443 [C₂₄H₁₉FN₆O₂+H]⁺.

The following examples serve to illustrate the invention withoutlimiting the scope thereof.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein X₁ and X₂ are independently N or C; X₃ and X₄ are independently N or CR²; provided that at least two of X₁, X₂, X₃, and X₄ are N;

is a single or double bond, as valency allows; R^(pa) is hydrogen, halogen, CN, optionally substituted C₁₋₆ alkyl, —OR^(A), —N(R^(B))₂, —NH—CO—R^(C); R^(C) is optionally substituted C₁₋₆ alkyl; R^(pb) is independently hydrogen, halogen, CN, —OR^(A), —N(R^(B))₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R^(1d) is optionally substituted six-membered heterocyclyl, —OR^(A), or —N(R^(B))₂; each instance of R² is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, —OR^(A), or —N(R^(B))₂, Ring A is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, or optionally substituted 5,6-bicyclic heteroaryl; each instance of R^(A) is independently hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R^(B) is independently hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group.
 2. The compound of claim 1, wherein the compound is of Formula (III-a), (III-b), (V-a), or (V-b):

wherein Z is —O— or —NR^(NZ)—; and each instance of R^(NZ) is independently hydrogen, optionally substituted C₁₋₆ alkyl, a nitrogen protecting group; or a pharmaceutically acceptable salt thereof.
 3. A compound of Formula (VII-a):

or a pharmaceutically acceptable salt thereof, wherein R^(1d) is optionally substituted six-membered heterocyclyl, —OR^(A), or —N(R^(B))₂; wherein R^(pa) is hydrogen, halogen, CN, optionally substituted C₁₋₆ alkyl, —OR^(A), —N(R^(B))₂, —NH—CO—R^(C); R^(C) is optionally substituted C₁₋₆ alkyl; R^(pb) is independently hydrogen, halogen, CN, —OR^(A), —N(R^(B))₂, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each instance of R^(A) is independently hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; each instance of R^(B) is independently hydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; and Ring A is optionally substituted phenyl, optionally substituted five-membered heteroaryl, optionally substituted six-membered heteroaryl, or optionally substituted 5,6-bicyclic heteroaryl.
 4. The compound of claim 3, wherein the compound is of Formula (VII-b):

or a pharmaceutically acceptable salt thereof, wherein Z is —O— or —NR^(NZ)—; and each instance of R^(NZ) is independently hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group.
 5. The compound of claim 1, wherein the compound is of Formula (IX-a):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 5, wherein the compound is of Formula (IX-b):

or a pharmaceutically acceptable salt thereof, wherein Z is —O— or —NR^(NZ)—; and each instance of R^(NZ) is independently hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protecting group.
 7. The compound of claim 3, wherein Z is —O— or —NR^(NZ)—, wherein R^(NZ) is hydrogen, optionally substituted C₁₋₆ alkyl, or unsubstituted C₁₋₆ alkyl.
 8. The compound of claim 1, wherein R^(pa) or R^(pb) is hydrogen or halogen.
 9. The compound of claim 1, wherein Ring A is optionally substituted five-membered heteroaryl with two heteroatoms selected from the group consisting of O, S, and N; or wherein Ring A is optionally substituted six-membered heteroaryl with one or two N; or wherein Ring A is of the formula:

wherein a indicates the point of attachment to the alkyne; each instance of R^(RA) is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionally substituted acyl, —CN, —OR^(AO), or —N(R^(AN))₂; each instance of R^(AO) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; each instance of R^(AN) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; and n1 is an integer of 1 to 5, inclusive.
 10. The compound of claim 9, wherein Ring A is one of the following formulae:

wherein a indicates the point of attachment to the alkyne; each instance of R^(RA) is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionally substituted acyl, —CN, —OR^(AO), or —N(R^(AN))₂; each instance of R^(AO) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R^(AN) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; and each instance of n3 is independently an integer of 1 to 4, inclusive.
 11. The compound of claim 10, wherein R^(RA) is —N(R^(AN))₂, —NHR^(AN), or —N(CH₃)R^(AN), wherein R^(AN) is optionally substituted C₁₋₆ alkyl, or unsubstituted C₁₋₆ alkyl.
 12. The compound of claim 10, wherein R^(RA) is of one of the following formulae:

wherein R^(RA1) is independently optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted phenyl, optionally substituted five- or six-membered heterocyclyl, optionally substituted five- or six-membered heteroaryl, —OR^(A), or —N(R^(B))₂; and each instance of R^(RA2) is independently optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₆ carbocyclyl, optionally substituted phenyl, optionally substituted five- or six-membered heterocyclyl, or optionally substituted five- or six-membered heteroaryl; or wherein R^(RA) is one of the following formulae: hydrogen, -Ph, —OH, —NH₂, —OCH₃, —OPh, —Cl, —CF₃, —CH₃,


13. A compound of the formula:

or a pharmaceutically acceptable salt thereof.
 14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound.
 15. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, the disease comprising a MNK-related disorder, an mTOR-related disorder, a PI3K-related disorder, a HER-related disorder, or a JAK-related disorder, wherein the PI3K-related disorder is a PIK3 α-related disorder, PIK3 β-related disorder, PIK3 γ-related disorder, or PIK3 δ-related disorder; wherein the HER-related disorder is a HER2-related disorder or a HER3-related disorder; wherein the JAK-related disorder is a JAK1-related disorder, a JAK2-related disorder, or a JAK3-related disorder; and wherein the MNK-related disorder is MNK1-related disorder or MNK2-related disorder.
 16. The method of claim 15 wherein the disease is cancer, an inflammatory disease, a neurodegenerative disease, or a metabolic disorder, wherein the cancer is solid tumor or hematological tumor, wherein the metabolic disorder is obesity or diabetes, and wherein the neurodegenerative disease is Alzheimer's disease, autism, or autism spectrum.
 17. A method of treating a MNK-related disorder in a subject, treating an mTOR-related disorder in a subject, treating a PI3K-related disorder in a subject, or treating a JAK-related disorder in a subject, comprising administering an effective amount of a compound of claim 1 to the subject, wherein the PI3K-related disorder is a PI3K α-related disorder, a PI3K β-related disorder, a PI3K γ-related disorder, or a PI3K δ-related disorder; wherein the JAK-related disorder is a JAK1-related disorder, a JAK2-related disorder, or a JAK3-related disorder.
 18. The compound of claim 4, wherein Ring A is optionally substituted 5,6-bicyclic heteroaryl.
 19. The compound of claim 18, wherein Ring A is optionally substituted 5,6-bicyclic heteroaryl with one, two, or three N atoms.
 20. The compound of claim 18, wherein Ring A is one of the following formulae:

wherein: a indicates the point of attachment to the alkyne; each instance of R^(RA) is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionally substituted acyl, —CN, —OR^(AO), or —N(R^(AN))₂; each instance of R^(AO) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; R^(AN) is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; and each instance of n4 is independently an integer of 1 to 5, inclusive.
 21. The compound of claim 20, wherein Ring A is selected from the group consisting of optionally substituted groups of the formula:


22. The compound of claim 18, wherein Ring A is selected from the group consisting of optionally substituted groups of the formula:


23. The compound of claim 18, wherein Ring A is selected from the group consisting of groups of the formula:

which are each optionally substituted with optionally substituted C₁₋₁₀ alkyl.
 24. The compound of claim 18, wherein Ring A is selected from the group consisting of groups of the formula:

which are each optionally substituted with optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl.
 25. The compound of claim 4, wherein Z is O and Ring A is optionally substituted 5,6-bicyclic heteroaryl.
 26. The compound of claim 4, wherein Ring A is optionally substituted 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or 5,6-bicyclic heteroaryl.
 27. The compound of claim 26, wherein Ring A is one of the following formulae:

wherein: a indicates the point of attachment to the alkyne; each instance of R^(RA) is independently hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionally substituted acyl, —CN, —OR^(AO), or —N(R^(AN))₂; each instance of R^(AO) is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or an oxygen protecting group; R^(AN) is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; each instance of n2 is independently an integer of 1 or 2; each instance of n3 is independently an integer of 1 to 4, inclusive; and each instance of n4 is independently an integer of 1 to 5, inclusive. 